Pyrido[4,3-b]indoles and methods of use

ABSTRACT

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[4,3-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/245,140, filed Sep. 23, 2009, and U.S. Provisional PatentApplication No. 61/245,259, filed Sep. 23, 2009, the disclosures of eachof which are hereby incorporated herein by reference in theirentireties.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia (such as cognitive impairment associated withschizophrenia (CIAS), positive symptoms, disorganized symptoms, andnegative symptoms of schizophrenia), anxiety, multiple sclerosis,stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression,attention-deficit disorder (ADD), attention-deficit hyperactivitydisorder (ADHD), depression and a variety of allergic diseases.Compounds that modulate these neurotransmitters may be usefultherapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., asantihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Hydrogenatedpyrido[4,3-b]indoles and uses thereof have been disclosed in PCT PatentApplication Nos. PCT/US2008/081390, PCT/US2009/032065 andPCT/US2009/038142. Hydrogenated pyrido[3,4-b]indoles and uses thereofhave been described in PCT/US2009/038138. All references disclosedherein and throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g. by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles are provided Compositions and kitscomprising the compounds are provided, as are methods of using andmaking the compounds. The compounds provided herein may find use intreating neurodegenerative diseases. Compounds of the invention may alsofind use in treating diseases and/or conditions in which modulation ofaminergic G protein-coupled receptors and/or neurite outgrowth may beimplicated in therapy. Compounds disclosed herein may find use in themethods disclosed herein, including use in treating, preventing,delaying the onset and/or delaying the development of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder and/ora neuronal disorder in an individual in need thereof, such as humans.

In one aspect, the invention provides a compound of the formula (I):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b)are taken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted orunsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl,acylamino or acyloxy or R^(3a) and R^(3b) are taken together with thecarbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(3a) and R^(10a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

n is 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, alkoxy, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(8(a-f))to form a substituted or unsubstituted methylene moiety or a moiety ofthe formula —OCH₂CH₂O—, or is taken together with a geminal R^(8(a-f))and the carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or is taken together with a vicinal R^(8(a-f)) andthe carbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or istaken together with a vicinal R^(8(a-f)) to form a bond provided thatwhen an R^(8(a-f)) is taken together with a vicinal R^(8(a-f)) to form abond, the geminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy orR^(10a) and R^(10b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(10a)and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(10a) and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety;

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxyor acylamino;

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety;

or a pharmaceutically acceptable salt thereof.

In one variation, compounds of the formula (I) are embraced, providedthat:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, X⁷-X¹⁰ is CR⁴, eachR^(2b), R^(3b), R^(10a) and R^(10b) are H, then (1) at least one ofR^(8(a-f)) is hydroxyl, alkyl or alky and/or (2) Q is other than asubstituted aryl or a substituted heteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷-X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (1) at least one ofR^(8(a-f)) is hydroxyl, alkyl or alkoxy and/or (2) Q is other than asubstituted aryl or a substituted heteroaryl.

In one aspect, compounds of the formula (I) contain one or more of thefollowing structural features: (1) at least one of X⁷, X⁸, X⁹ and X¹⁰ isN; (2) at least one of R^(8(a-f)) is other than H, such as a hydroxyl,alkyl or alkoxy moiety; and (3) Q is other than a substituted aryl orheteroaryl moiety.

In another aspect, the invention provides a compound of formula (A):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b)are taken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted orunsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl,acylamino or acyloxy or R^(3a) and R^(3b) are taken together with thecarbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(3a) and R^(10a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m, and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,alkoxy, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstitutedC₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or istaken together with a geminal R^(8(a-d)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-d)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety;

each R^(10a) and R^(10b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy orR^(10a) and R^(10b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(10a)and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(10a) and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety;

each R¹¹ and R¹² is independently H, halo, alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₃-C₈ cycloalkyl, carboxy,carbonylalkoxy or C₁-C₈ perhaloalkyl and the

bond indicates the presence of either an E or Z double bondconfiguration, or R¹¹ and R¹² are taken together to form a bond or aretaken together with the carbon atoms to which they are attached to forma substituted or unsubstituted C₃₋₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy, cyano, alkynylor acylamino;

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety.

In one variation, compounds of the formula (A) are embraced, providedthat:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, X⁷-X¹⁰ is CR⁴, eachR^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least one of R¹¹ or R¹²is alkoxy, and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷-X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least one of R¹¹ or R¹²is alkoxy, and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl;

or a pharmaceutically acceptable salt thereof.

It is understood that variations and aspects that are described hereinfor one formula, but which are applicable to another formula, applyequally to the other formula the same as if each and every variation andaspect were specifically and individually listed. For example, where aparticular description of moiety Q is provided for one formula, it isunderstood that the same description for Q may be applied to the otherformulae provide herein, where applicable (e.g., where the otherformulae allow for such Q moieties). In addition, any proviso orprovision that is described for one formula may also be applied toanother formula, where applicable. For example, provisions (A)-(G) offormula (I) in one aspect apply equally to formula (I-1) or any otherformula detailed herein, where applicable, the same as if each provisionwere specifically and individually listed.

In another aspect, the invention provides a method of treating acognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder or a neuronal disorder in an individual comprisingadministering to an individual in need thereof an effective amount of acompound described herein, such as a compound of the formula (I) orpharmaceutically acceptable salt thereof.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, and any tautomers or other forms of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. Unless olefin geometry isexplicitly indicated, substituted olefinic bonds may be present as cis(Z) or trans (E) isomeric forms, or as mixtures thereof. In addition,where a specific stereochemical form is depicted, it is understood thatother stereochemical forms are also embraced by the invention. All formsof the compounds are also embraced by the invention, such as crystallineor non-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof. Compositions comprising a mixture of compounds of the inventionin any ratio are also embraced by the invention, including mixtures oftwo or more stereochemical forms of a compound of the invention in anyratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention. Compounds as detailedherein or a pharmaceutically acceptable salt thereof are also providedfor the manufacture of a medicament for the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, schizophrenia,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, stroke, head trauma and spinal cord injury. Compounds of theinvention that stimulate neurite outgrowth may have a benefit in thesesettings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)), serotoninreceptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇), dopaminereceptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂ and/or H₃).In another variation, at least two of the following receptors aremodulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)),serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇),dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂and/or H₃). In another variation, at least three of the followingreceptors are modulated: adrenergic receptor (e.g., α_(1D), α_(2A)and/or α_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆and/or 5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor(e.g., H₁, H₂ and/or H₃). In another variation, each of the followingreceptors is modulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/orα_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g.,H₁, H₂ and/or H₃). In another variation, at least one of the followingreceptors is modulated: α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C),5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. In another variation, at least twoor three or four or five or six or seven or eight or nine or ten oreleven of the following receptors are modulated: α_(1D), α_(2A), α_(2B),5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. In aparticular variation, at least dopamine receptor D_(2L) is modulated. Inanother particular variation, at least dopamine receptor D_(2L) andserotonin receptor 5-HT_(2A) are modulated. In a further particularvariation, at least adrenergic receptors α_(1D), α_(2A), α_(2B) andserotonin receptor 5-HT₆ are modulated. In another particular variation,at least adrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor5-HT₆ and one or more of serotonin receptor 5-HT₇, 5-HT_(2A), 5-HT_(2C)and histamine receptor H₁ and H₂ are modulated. In a further particularvariation, histamine receptor H₁ is modulated. In another variation,compounds of the invention exhibit any receptor modulation activitydetailed herein and further stimulate neurite outgrowth and/orneurogenesis and/or enhance neurotrophic effects.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

The term “about” as used herein refers to the usual range of variationfor the respective value readily known to the skilled person in thistechnical field. Reference to “about” a value or parameter hereinincludes (and describes) embodiments that are directed to that value orparameter per se. For example, description referring to “about X”includes description of “X”.

As used herein, the term “aminergic G protein-coupled receptors” refersto a family of transmembrane proteins involved in cellularcommunication. Aminergic G protein coupled receptors are activated bybiogenic amines and represent a subclass of the superfamily of G proteincoupled receptors, which are structurally characterized by seventransmembrane helices. Aminergic G protein-coupled receptors include butare not limited to adrenergic receptors, serotonin receptors, dopaminereceptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) and/orreduces or eliminates or increases or enhances or mimics an activity ofa α₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) in areversible or irreversible manner. In some aspects, the adrenergicreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some aspects, theadrenergic receptor modulator reduces an activity of an adrenergicreceptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as compared to the corresponding activity in thesame subject prior to treatment with the adrenergic receptor modulatoror compared to the corresponding activity in other subjects notreceiving the adrenergic receptor modulator. In some aspects, theadrenergic receptor modulator enhances an activity of an adrenergicreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatoris capable of binding to the active site of an adrenergic receptor(e.g., a binding site for a ligand). In some embodiments, the adrenergicreceptor modulator is capable of binding to an allosteric site of anadrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D₁)and/or a dopamine-2 (D₂) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D₁) and/or adopamine-2 (D₂) receptor in a reversible or irreversible manner.Dopamine D₂ receptors are divided into two categories, D_(2L) andD_(2S), which are formed from a single gene by differential splicing.D_(2L) receptors have a longer intracellular domain than D_(2S). In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A) and/or a 5-HT_(2B)and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-HT₆ and/or a5-HT₇ receptor or reduces or eliminates or increases or enhances ormimics an activity of a 5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A)and/or a 5-HT_(2B) and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄and/or a 5-HT₆ and/or a 5-HT₇ receptor in a reversible or irreversiblemanner. In some embodiments, the serotonin receptor modulator inhibitsbinding of a ligand by at least about or about any one of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assaysdescribed herein. In some embodiments, the serotonin receptor modulatorreduces an activity of a serotonin receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator enhances an activity of a serotonin receptor by at least aboutor about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100or 200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the serotoninreceptor modulator or compared to the corresponding activity in othersubjects not receiving the serotonin receptor modulator. In someembodiments, the serotonin receptor modulator is capable of binding tothe active site of a serotonin receptor (e.g., a binding site for aligand). In some embodiments, the serotonin receptor modulator iscapable of binding to an allosteric site of a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa histamine receptor or reduces or eliminates or increases or enhancesor mimics an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator binds to or inhibits binding of a ligand to ahistamine H₁ and/or H₂ and/or H₃ receptor or reduces or eliminates orincreases or enhances or mimics an activity of a histamine H₁ and/or H₂and/or H₃ receptor in a reversible or irreversible manner. In someembodiments, the histamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same individual prior to treatment withthe histamine receptor modulator or compared to the correspondingactivity in like individuals not receiving the histamine receptormodulator. In some embodiments, the histamine receptor modulatorenhances an activity of a histamine receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200%or 300% or 400% or 500% or more as compared to the correspondingactivity in the same individual prior to treatment with the histaminereceptor modulator or compared to the corresponding activity in likeindividuals not receiving the histamine receptor modulator. In someembodiments, the histamine receptor modulator is capable of binding tothe active site of a histamine receptor (e.g., a binding site for aligand). In some embodiments, the histamine receptor modulator iscapable of binding to an allosteric site of a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to human, bovine, primate,equine, canine, feline, porcine, and ovine animals. Thus, the inventionfinds use in both human medicine and in the veterinary context,including use in agricultural animals and domestic pets. The individualmay be a human who has been diagnosed with or is suspected of having acognitive disorder, a psychotic disorder, a neurotransmitter-mediateddisorder and/or a neuronal disorder. The individual may be a human whoexhibits one or more symptoms associated with a cognitive disorder, apsychotic disorder, a neurotransmitter-mediated disorder and/or aneuronal disorder. The individual may be a human who has a mutated orabnormal gene associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who is genetically or otherwisepredisposed to developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with a disease or condition. In one variation, beneficial ordesired clinical results include, but are not limited to, alleviation ofa symptom and/or diminishment of the extent of a symptom and/orpreventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g. HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis(ALS), autism, ADHD, ADD, mild cognitive impairment (MCI), stroke,traumatic brain injury (TBI) and age-associated memory impairment(AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia, ADHD, ADD, anxiety, multiple sclerosis,stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MCI), injury-related mild cognitiveimpairment (MCI), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, ADHD, ADD,anxiety or depression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g. large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. Aβ appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes [Tanzi etal., Neurobiol. Dis. (1996), 3:159-168; Hardy, Ann. Med. (1996),28:255-258]. Diseased-linked mutations in these genes result inincreased production of the 42-amino acid form of Aβ, the predominantform found in amyloid plaques. Mitochondrial dysfunction has also beenreported to be an important component of Alzheimer's disease [Bubber etal., Mitochondrial abnormalities in Alzheimer brain: MechanisticImplications, Ann Neurol. (2005), 57(5):695-703; Wang et al, Insightsinto amyloid-β-induced mitochondrial dysfunction in Alzheimer disease,Free Radical Biology & Medicine (2007), 43:1569-1573; Swerdlow et al.,Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol. (2002),53:341-385; Reddy et al., Are mitochondria critical in the pathogenesisof Alzheimer's disease?, Brain Res. Rev. (2005), 49(3):618-32]. It hasbeen proposed that mitochondrial dysfunction has a causal relationshipwith neuronal function (including neurotransmitter synthesis andsecretion) and viability. Compounds which stabilize mitochondria maytherefore have a beneficial impact on Alzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntingtin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) [Reisberg et al., Am. J. Psychiatry(1982), 139:1136-1139] which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, i.e., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons[Prichep et al., Neurobiol. Aging (1994), 15:85-90].

As used herein, the term “mild cognitive impairment” or “MCI” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MCI havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MCI is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MCI alsoencompasses injury-related MCI, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (i.e.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (i.e., where a nerveor nerves have been torn or ripped) or spinal cord injury (i.e., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (i.e., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

“Cognitive impairment associated with schizophrenia” or “CIAS” includesneuropsychological deficits in attention, working memory, verballearning, and problem solving. These deficits are believed to be linkedto impairment in functional status (e.g., social behavior, workperformance, and activities of daily living).

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein, attention-deficit hyperactivity disorder (ADHD) is themost common child neuropsychiatric condition present in school-agedchildren, affecting about 5-8% of this population. ADHD refers to achronic disorder that initially manifests in childhood and ischaracterized by hyperactivity, impulsivity, and/or inattention. ADHD ischaracterized by persistent patterns of inattention and/orimpulsivity-hyperactivity that are much more extreme than is observed inindividuals at the same developmental level or stage. There isconsiderable evidence, from family and twin studies, that ADHD has asignificant genetic component. This disorder is thought to be due to aninteraction of environmental and genetic factors. ADHD includes allknown types of ADHD. For example, Diagnostic & Statistical Manual forMental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD,Combined Type which is characterized by both inattention andhyperactivity-impulsivity symptoms; (2) ADHD, Predominantly InattentiveType which is characterized by inattention but nothyperactivity-impulsivity symptoms; and (3) ADHD, PredominantlyHyperactive-Impulsive Type which is characterized byHyperactivity-impulsivity but not inattention symptoms.

As used herein, attention-deficit disorder (ADD) refers to a disorder inprocessing neural stimuli that is characterized by distractibility andimpulsivity that can result in inability to control behavior and canimpair an individual's social, academic, or occupational function anddevelopment. ADD may be diagnosed by known methods, which may includeobserving behavior and diagnostic interview techniques.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anthercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. A pharmaceutically acceptable salt intends ionicinteractions and not a covalent bond. As such, an N-oxide is notconsidered a salt. Such salts, for example, include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, oxalic acid,propionic acid, succinic acid, maleic acid, tartaric acid and the like;(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase. Acceptable organic bases include ethanolamine, diethanolamine,triethanolamine and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like. Further examples ofpharmaceutically acceptable salts include those listed in Berge et al.,Pharmaceutical Salts, J. Pharm. Sci. (1977), 66(1):1-19.Pharmaceutically acceptable salts can be prepared in situ in themanufacturing process, or by separately reacting a purified compound ofthe invention in its free acid or base form with a suitable organic orinorganic base or acid, respectively, and isolating the salt thus formedduring subsequent purification. It should be understood that a referenceto a pharmaceutically acceptable salt includes the solvent additionforms or crystal forms thereof, particularly solvates or polymorphs.Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and solubility. Various factors suchas the recrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring. Cycloalkenyl is a subset ofalkenyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A more preferred cycloalkenyl is anunsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms(a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to 10 carbon atoms and morepreferably 3 to 8 carbon atoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents s including, but not limited to, substituents such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. Aheterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 2 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano,halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. A“substituted aralkyl” refers to a residue in which an aryl moiety isattached to a substituted alkyl residue and wherein the aralkyl groupmay be attached to the parent structure at either the aryl or the alkylresidue. When an aralkyl is connected to the parent structure via thealkyl moiety, it may also be referred to as an “alkaryl”. Moreparticular alkaryl groups are those having 1 to 3 carbon atoms in thealkyl moiety (a “C₁-C₃ alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-aryl, —NRSO₂-substituted aryl,—NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic,and —NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O) O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure S compound means that the composition contains nomore than 15% or no more than 10% or no more than 5% or no more than 3%or no more than 1% of the R form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, salts and solvates of the compoundsdescribed as histamine receptor modulators.

The invention embraces a compound of the formula (I):

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b)are taken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted orunsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl,acylamino or acyloxy or R^(3a) and R^(3b) are taken together with thecarbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(3a) and R^(10a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

n is 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, alkoxy, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(8(a-f))to form a substituted or unsubstituted methylene moiety or a moiety ofthe formula —OCH₂CH₂O—, or is taken together with a geminal R^(8(a-f))and the carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or is taken together with a vicinal R^(8(a-f)) andthe carbon atoms to which they are attached to form a substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or istaken together with a vicinal R^(8(a-f)) to form a bond provided thatwhen an R^(8(a-f)) is taken together with a vicinal R^(8(a-f)) to form abond, the geminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy orR^(10a) and R^(10b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(10a)and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(10a) and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety;

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy, cyano, alkynylor acylamino;

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety.

In one variation, compounds of the formula (I) are embraced, providedthat:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene

(—CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, each R^(2b), R^(3b), R^(10a) andR^(10b) are H, then (1) at least one of R^(8(a-f)) is hydroxyl, alkyl oralkoxy and/or (2) Q is other than a substituted aryl or a substitutedheteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b), are H, then (1) at least one ofR^(8(a-f)) is hydroxyl, alkyl or alkoxy and/or (2) Q is other than asubstituted aryl or a substituted heteroaryl.

In one variation, compounds of the formula (I) are provided where atleast one of R^(8(a-f)) is a substituted C₁-C₈ alkyl where the C₁-C₈alkyl is substituted with a carbonylalkoxy, carboxyl or acylaminomoiety.

In another variation of formula (I), at least one R^(3a) and R^(3b) isaryl. In a particular variation of formula (I), at least one of R^(3a)and R^(3b) is phenyl.

In one variation of formula (I), provision (i) applies such that R¹ andR^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety. In one variation of formula (I),provision (ii) applies such that R¹ and R^(3a) are taken together toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety.In still another variation of formula (I), provision (iii) applies suchthat R¹ and R^(10a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety. In yet another variationof formula (I), provision (iv) applies such that R^(2a) and R^(3a) aretaken together to form a methylene (—CH₂—) moiety or an ethylene(—CH₂CH₂—) moiety. In a further variation of formula (I), provision (v)applies such that R^(3a) and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety. Inany of provisions (i) -(v), in one variation, a five member ring isprovided by the provision, such as when provision (i) applies and R¹ andR^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety orwhen provision (ii) applies and R¹ and R^(3a) are taken together to forman ethylene (—CH₂CH₂—) moiety. In any of provisions (i)-(v), in onevariation, a six member ring is provided by the provision, such as whenprovision (i) applies and R¹ and R^(2a) are taken together to form abutylene (—CH₂CH₂CH₂CH₂—) moiety or when provision (ii) applies and R¹and R^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety.

In one variation, R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In another variation,each R^(2a) and R^(2b) is independently H, hydroxyl, alkoxy orsubstituted or unsubstituted C₁-C₈ alkyl. In yet another variation, eachR^(3a) and R^(3b) is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted orunsubstituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) andR^(3b) are taken together to form a cycloalkyl moiety or a carbonylmoiety. In still another variation, each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbonto which it is attached and a geminal R^(8( a-f)) to form a cycloalkylmoiety or a carbonyl moiety, is taken together with a geminal R^(8(a-f))to form a methylene or a substituted methylene, is taken together with avicinal R^(8(a-f)) and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R^(8(a-f)) toform a bond, provided that when an R^(8(a-f)) is taken together with avicinal R^(8(a-f)) to form a bond, the geminal R^(8(a-f)) is other thanhydroxyl. In a further variation, R¹⁰ is H, hydroxyl, alkoxy or asubstituted or unsubstituted C₁-C₈ alkyl. In another variation, eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently C₁-C₈alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety.

Compounds of the formula (I) are also provided in one variation where qis 0, m is 1 and each R^(8c), R^(8d), R^(8e) and R^(8f) is H. In onesuch variation, compounds of the formula (I) are provided where q is 0,m is 1 and each R^(8c), R^(8d), R^(8e) and R^(8f) is H and Q is asubstituted or unsubstituted aryl, such as phenyl, or a substituted orunsubstituted heteroaryl, such as pyridyl. In a further variation,compounds of the formula (I) are provided where q is 0, m is 1 and eachR^(8c), R^(8d), R^(8e) and R^(8f) is H, X⁷, X⁸ and X¹⁰ are CR⁴ where R⁴is H and X⁹ is CR⁴ where R⁴ is H, halo or unsubstituted C₁-C₈alkyl. In amore particular variation, compounds of formula (I) are provided where qis 0, m is 1 and each R^(8c), R^(8d), R^(8e) and R^(8f) is H, X⁷, X⁸ andX¹⁰ are CR⁴ where R⁴ is H, X⁹ is CR⁴ where R⁴ is H, halo orunsubstituted C₁-C₈alkyl and Q is a substituted or unsubstituted aryl,such as phenyl, or a substituted or unsubstituted heteroaryl, such aspyridyl.

Compounds of the formula (I) are also provided in one variation where qis 0, m is 1 and at least one of R^(8c), R^(8d), R^(8e) and R^(8f) is anunsubstituted C₁-C₈alkyl or hydroxyl. In one such variation, q is 0, mis 1, R^(8e) and R^(8d) are each H and at least one of R^(8e) and R^(8f)is an unsubstituted C₁-C₈alkyl or hydroxyl. Compounds of thesevariations may be further defined by one or more of the followingstructural features: X⁷, X⁸ and X¹⁰ are CR⁴ where R⁴ is H; X⁹ is CR⁴where R⁴ is H, halo or unsubstituted C₁-C₈alkyl; and Q is a substitutedor unsubstituted aryl, such as phenyl, or a substituted or unsubstitutedheteroaryl, such as pyridyl.

Also provided are methods of using compounds described herein, such ascompounds of formula (I), in various therapeutic applications.

In another variation, the invention embraces compounds of the formulae(I)-(VI), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and(Ii-7), (II-1), (III-1), (IV-1), (V-1) and (VI-1), (A)-(F) and(A-1)-(A-4), or any variation herein, or a salt or solvate herein. In aparticular variation, the invention embraces methods of using compoundsof the formulae (I)-(VI), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4),(Ii-5), (Ii-6) and (Ii-7), (II-1), (III-1), (IV-1), (V-1) and (VI-1),(A)-(F) and (A-1)-(A-4), or any variation herein, or a salt or solvateherein as detailed herein. Compounds of the formulae (I)-(VI),(Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and (Ii-7),(II-1), (III-1), (IV-1), (V-1) and (VI-1), (A)-(F) and (A-1)-(A-4) aredescribed as new histamine receptor modulators. Compounds of theinvention may also find use in treating neurodegenerative diseases.

In one variation, the invention embraces compounds of the formulae(I)-(VI), (Ia)-(Ik), (Ii-1), (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and(Ii-7), (II-1), (III-1), (IV-1), (V-1) and (VI-1), (A)-(F) and(A-1)-(A-4), or any variation herein or a salt or solvate herein. Inanother variation, the invention embraces methods of using andadministering compounds of the formulae (I)-(VI), (Ia)-(Ik), (Ii-1),(Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and (Ii-7), (II-1), (III-1),(IV-1), (V-1) and (VI-1), (A)-(F) and (A-1)-(A-4), or any variationherein or a salt or solvate herein as detailed herein.

In one variation, this invention embraces compounds of formulae(Ia)-(Ih):

wherein X⁷, X⁸, X⁹, X¹⁰, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a),R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(10a), R^(10b), Q, m and q areas defined for formula (I);

R⁹ is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy,carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl,alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino,sulfonyl, carbonyl, aminoacyl and aminocarbonylamino moiety;

s is an integer from 0 to 5; and

t is an integer from 0 to 4;

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety.

In one variation, compounds of the formulae (Ia)-(Ih) are providedherein, provided that:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, eachR^(2b), R^(3b), R^(10a) and R^(10b) are H, then, (1) at least one ofR^(8(a-f)) is hydroxyl, alkyl or alkoxy and/or (2) Q is other than asubstituted aryl or a substituted heteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (1) at least one ofR^(8(a-f)) is hydroxyl, alkyl or alkoxy and/or (2) Q is other than asubstituted aryl or a substituted heteroaryl.

In one variation, this invention embraces compounds of formulae (I),(Ia)-(Ih), (Ij), (Ik) and (A), wherein at least one of X⁷, X⁸, X⁹ andX¹⁰ is N. In another variation, this invention embraces compounds offormulae (I), (Ia)-(Ih), (Ij), (Ik), and (A), wherein at least one ofX⁷, X⁸, X⁹ and X¹⁰ is N and each of R^(2a), R^(2b), R^(3b), R^(10a) andR^(10b) are H.

In one variation, compounds of the formula (I), (Ia)-(Ih), (Ij), (Ik)and (A), where applicable, have one or more of the following structuralfeatures: (1) at least one of X⁷, X⁸, X⁹ and X¹⁰ is N; (2) at least oneof the R⁸ moieties present is other than H (e.g., where q, m and n areeach 1, at least one of R^(8a)-R^(8f) is other than H, such as when atleast one of the R⁸ moieties is an alkyl, alkoxy or hydroxyl group); (3)Q is other than a substituted aryl or substituted heteroaryl; and (4) R¹is a substituted or unsubstituted C₁-C₈ alkyl (such as methyl) or acyl.

In one variation, the invention embraces compounds of any one or more offormulae (Ib), (Ie), (Ii), (Ij) and (Ik):

wherein Q, X⁷, X⁸, X⁹, X¹⁰, R⁴, R¹, R^(2a), R^(2b), R^(3a), R^(3b),R^(10a), R^(10b), R^(8c), R^(8d), R^(8e) and R^(8f), where applicable,are as defined for formula (I);

each R⁹ is independently halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylaminomoiety;

s is an integer from 0 to 5;

and t is an integer from 0 to 4.

Although R⁹ of formulae (Ij) and (Ik) is attached to a specific positionof the pyridyl group, in other embodiments, analogous structures areprovided wherein R⁹ is attached to the pyridyl ring at any availablecarbon atom.

In another variation, compounds of formula (Ii-1) are provided:

wherein X⁷, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) areas defined for formula (I);

R⁴ is halo (e.g., chloro) or alkyl (e.g., CH₃, ethyl, i-propyl ort-butyl);

R^(8e) and R^(8f) are independently H, OH or CH₃; and

Q is substituted or unsubstituted aryl or heteroaryl,

provided that: (i) when X⁷ is N, R^(8e) and R^(8f) are H; and (ii) whenX⁷ is CR⁴ where R⁴ is H, R^(8e) is OH and R^(8f) is H or CH₃. In oneembodiment of formula (Ii-1), Q is substituted or unsubstituted pyridyl.In one such variation, of formula (Ii-1), R⁴ is halo. When R⁴ is halo,in one aspect it is chloro. In another variation of formula (Ii-1), R⁴is a C₁-C₄ alkyl, such as methyl, ethyl, propyl or butyl. In a furthervariation of formula (Ii-1), R¹ is H or a substituted or unsubstitutedC₁-C₈ alkyl (such as methyl).

In one variation, compounds of formula (II-1) are provided wherein X⁷,R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) are as definedfor formula (I);

R⁴ is halo;

R^(8e) and R^(8f) are independently H, OH or CH₃; and

Q is substituted or unsubstituted aryl or heteroaryl, provided that: (i)when X⁷ is N, R^(8e) and R^(8f) are H; and (ii) when X⁷ is CR⁴ where R⁴is H, R^(8e) is OH and R^(8f) is H or CH₃. In one embodiment of formula(Ii-1), Q is substituted or unsubstituted pyridyl. In one embodiment offormula (Ii-1), R⁴ is chloro.

The invention in another variation embraces compounds of any one or moreof formula (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and (Ii-7):

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) are asdefined for formula (I);

R⁴ is halo (e.g., chloro) or alkyl (e.g., CH₃, ethyl, i-propyl ort-butyl);

R⁹ is H or CH₃, and

R^(8f) is H or CH₃.

In one such variation of any of formula (Ii-2)-(Ii-7), R⁴ is halo. WhenR⁴ is halo, in one aspect it is chloro. In another variation of any offormula (Ii-2)-(Ii-7), R⁴ is a C₁-C₄ alkyl, such as methyl, ethyl,propyl or butyl. In a further variation of any of formula (Ii-2)-(Ii-7),R¹ is H or a substituted or unsubstituted alkyl.

Although R⁹ of formulae (Ii-2), (Ii-3), (Ii-5) and (Ii-6) is attached toa specific position of the pyridyl group, in other embodiments,analogous structures are provided wherein R⁹ is attached to the pyridylring at any available carbon atom. Likewise, although R⁹ of formulae(Ii-4) and (Ii-7) may be attached at any available position of thepyridyl ring, in another embodiment, analogous independent structuresare provided where R⁹ is individually attached to each such availableposition.

The invention in another variation embraces compounds of any one or moreof formula (Ii-2), (Ii-3), (Ii-4), (Ii-5), (Ii-6) and (Ii-7), whereinR¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) are as definedfor formula (I), R⁴ is halo; R⁹ is H or CH₃, and R^(8f) is H or CH₃. Inone variation of compounds of any one or more of formula (Ii-2), (Ii-3),(Ii-4), (Ii-5), (Ii-6) and (Ii-7), R⁴ is chloro.

The invention also embraces compounds of formula (A):

or a salt or solvate thereof, wherein:

R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), X⁷, X⁸, X⁹, X¹⁰,Q, m and q are as defined for formula (I);

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,alkoxy, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstitutedC₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or istaken together with a geminal R^(8(a-d)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-d)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety; and

each R¹¹ and R¹² is independently H, halo, alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₃-C₈ cycloalkyl, carboxy,carbonylalkoxy or C₁-C₈ perhaloalkyl and the

bond indicates the presence of either an E or Z double bondconfiguration, or R¹¹ and R¹² are taken together to form a bond or aretaken together with the carbon atoms to which they are attached to forma substituted or unsubstituted C₃₋₈ cycloalkenyl or substituted orunsubstituted heterocyclyl moiety;

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety.

In one variation, compounds of the formula (A) are embraced, providedthat:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, eachR^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least one of R¹¹ or R¹²is alkoxy, and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least one of R¹¹ or R¹²is alkoxy, and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl;

or a pharmaceutically acceptable salt thereof.

In one variation, compounds of the formula (A) are provided where atleast one of R^(8(a-d)) is a substituted C₁-C₈ alkyl where the C₁-C₈alkyl is substituted with a carbonylalkoxy, carboxyl or acylaminomoiety.

In another variation of formula (A), at least one R^(3a) and R^(3b) isaryl. In a particular variation of formula (A), at least one of R^(3a)and R^(3b) is phenyl.

In still another variation of formula (A), each R¹¹ and R¹² isindependently H, halo, alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₃-C₈ cycloalkyl, carboxy, carbonylalkoxy or C₁-C₈perhaloalkyl and the

bond indicates the presence of either an E or Z double bondconfiguration, or R¹¹ and R¹² are taken together to form a bond.

In one variation of formula (A), R¹¹ is H, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted C₁-C₈ perhaloalkyl and R¹² is H,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, or substituted or unsubstituted C₁-C₈ perhaloalkyl, oris taken together with R¹¹ and the carbon atoms to which they areattached to form a substituted or unsubstituted C₃-C₈ cycloalkenylmoiety

In one variation of formula (A), R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In another variationof formula (A), each R^(2a) and R^(2b) is independently H, hydroxyl,alkoxy or substituted or unsubstituted C₁-C₈ alkyl. In yet anothervariation of formula (A), each R^(3a) and R^(3b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl,alkoxy, substituted or unsubstituted amino, cycloalkyl, acylamino oracyloxy or R^(3a) and R^(3b) are taken together to form a cycloalkylmoiety or a carbonyl moiety. In still another variation, each R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is takentogether with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R^(8(a-f)) to form a bond,the geminal R^(8(a-f)) is other than hydroxyl. In a further variation offormula (A), R¹⁰ is H, hydroxyl, alkoxy or a substituted orunsubstituted C₁-C₈ alkyl. In another variation of formula (A), eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently C₁-C₈alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety.

In one variation of formula (A), q is 0. In another variation of formula(A), m is 0. In a particular variation of formula (A), both q and m are0. When both q and m are 0, in one aspect, at least one of R¹¹ and R¹²is an unsubstituted C₁-C₈alkyl, such as methyl. In one such variation offormula (A), both q and m are 0, R¹¹ is H and R¹² is an unsubstitutedC₁-C₈alkyl, such as methyl. Compounds of these variations may be furtherdefined by one or more of the following structural features: X⁷, X⁸ andX¹⁰ are CR⁴ where R⁴ is H; X⁹ is CR⁴ where R⁴ is H, halo orunsubstituted C₁-C₈alkyl; Q is a substituted or unsubstituted aryl, suchas phenyl, or a substituted or unsubstituted heteroaryl, such aspyridyl; the R^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) and R^(3b)residues that are not bound to form a five or six member ring are eachH, provided that one of provisions (i)-(v) applies.

The invention also embraces compounds of formulae (A-1), (A-2), (A-3)and (A-4):

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a), R^(8b), R^(8c),R^(8d), R^(10a), R^(10b), R¹¹, R¹², X⁷, X⁸, X⁹, X¹⁰ and Q are as definedfor formula (A); and

provided that the compound conforms to one of provisions (i)-(v): (i) R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; (ii) R¹ and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; (iii) R¹ and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;(iv) R^(2a) and R^(3a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety; and (v) R^(3a) and R^(10a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety.

In one variation, compounds of the formulae (A-1), (A-2), (A-3) and(A-4) are embraced, provided that:

(A) when R^(2a) and R^(3a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, eachR^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least one of R¹¹ or R¹²is alkoxy and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl; and

(B) when R¹ and R^(3a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, X⁷—X¹⁰ is CR⁴, each R^(2a),R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) at least one ofR^(8(a-d)) is hydroxyl or alkoxy; and/or (ii) at least one of R¹¹ or R¹²is alkoxy; and/or (iii) Q is other than a substituted aryl or asubstituted heteroaryl.

All variations referring to the formulae herein, such as formulae (I),(Ia)-(Ih), (A), (A-1)-(A-4), where applicable, may apply equally to anyof formulae (II)-(VI) and (B)-(F) below, or any other formula detailedherein, such as formulae (Ib)-(Ik), (Ii-1)-(Ii7) and (III-1)-(VII-1) thesame as if each and every variation were specifically and individuallylisted.

In another variation, the invention embraces compounds of formulae(II)-(VI):

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a), R^(8b), R^(8c),R^(8d), R^(8e), R^(8f), R^(10a), R^(10b), X⁷, X⁸, X⁹, X¹⁰, Q, m, n and qare as defined for formula (I); p is 1 or 2; or a salt or solvatethereof. In one variation, each R⁴ is independently H, halo, orsubstituted or unsubstituted C₁-C₈ alkyl.

In one variation, this invention embraces compounds of formulae(II)-(VII), wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N. In anothervariation, this invention embraces compounds of formulae (II)-(VII),wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is N and each R^(2a), R^(2b),R^(3b), R^(10a) and R^(10b) are H.

In one variation, compounds of the formulae (II)-(VI) are embraced,provided that:

(A) when the compound is of the formula (IV) where p is 1 or 2, X⁷—X¹⁰is CR⁴, each R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) atleast one of R^(8(a-d)) is hydroxyl or alkoxy, and/or (ii) at least oneof R¹¹ or R¹² is alkoxy and/or (iii) Q is other than a substituted arylor a substituted heteroaryl; and

(B) when the compound is of the formula (V) where p is 1 or 2, X⁷—X¹⁰ isCR⁴, each R^(2a), R^(2b), R^(3b), R^(10a) and R^(10b) are H, then (i) atleast one of R^(8(a-d)) is hydroxyl or alkoxy; and/or (ii) at least oneof R¹¹ or R¹² is alkoxy; and/or (iii) Q is other than a substituted arylor a substituted heteroaryl.

The invention also embraces compounds of any one or more of formulae(II-1), (III-1), (IV-1), (V-1) and (VI-1):

wherein Q, X⁷, X⁸, X⁹, X¹⁰, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(8c), R^(8d), R^(8e), R^(8f), and p, where applicable, are asdefined for formula (III), (IV), (V), (VI) and (VII) respectively.

In one aspect, the invention embraces compounds of the formulae (II-1),(III-1), (IV-1), (V-1) and (VI-1) wherein each X⁷, X⁸ and X¹⁰ is CR⁴where R⁴ is H. In another aspect, the invention embraces compounds ofthe formulae (II-1), (III-1), (IV-1), (V-1) and (VI-1) wherein each X⁷,X⁸ and X¹⁰ is CR⁴ where R⁴ is H, X⁹ is CR⁴ where R⁴ is as defined forformulae (II), (III), (IV), (V) and (VI) respectively, and Q issubstituted or unsubstituted aryl or heteroaryl. In another aspect, theinvention embraces compounds of the formulae (II-1), (III-1), (IV-1),(V-1) and (VI-1) wherein each X⁷, X⁸ and X¹⁰ is CR⁴ where R⁴ is H, X⁹ isCR⁴ where R⁴ is halo (e.g., chloro) or alkyl (e.g., CH₃, ethyl, i-propylor t-butyl), R^(8c) is OH, R^(8d) is H or CH₃, each R^(8e) and R^(8f) isH, and Q is substituted or unsubstituted aryl or heteroaryl. In onevariation of formula (IV-1) or (VI-1), R¹ is H or a substituted orunsubstituted C₁-C₈ alkyl (such as methyl).

In another aspect, the invention embraces compounds of the formulae(II-1), (III-1), (IV-1), (V-1) and (VI-1) wherein each X⁷, X⁸ and X¹⁰ isCR⁴ where R⁴ is H, X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) or alkyl(e.g., CH₃, ethyl, i-propyl or t-butyl), R^(8c) is OH, R^(8d) is H orCH₃, each R^(8e) and R^(8f) is H, and Q is substituted or unsubstitutedpyridyl.

In one aspect, the invention embraces compounds of the formulae (II-1),(III-1), (IV-1), (V-1) and (VI-1) wherein X⁸ and X¹⁰ are H and X⁹ is CR⁴and Q is substituted or unsubstituted aryl or heteroaryl. In anotheraspect, the invention embraces compounds of the formulae (II-1),(III-1), (IV-1), (V-1) and (VI-1) wherein X⁷ is as defined for formulae(II), (III), (IV), (V) and (VI) respectively, each X⁸ and X¹⁰ is CR⁴where R⁴ is H, X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) or alkyl (e.g.,CH₃, ethyl, i-propyl or t-butyl), R^(8c) and R^(8c) are independently H,OH or CH₃, each R^(8e) and R^(8f) is H, and Q is substituted orunsubstituted aryl or heteroaryl, provided that: (i) when X⁷ is N,R^(8c) and R^(8d) are H; and (ii) when X⁷ is CR⁴ where R⁴ is H, R^(8c)is OH and R^(8d) is H or CH₃. In one such embodiment, Q is substitutedor unsubstituted pyridyl.

This invention also embraces compounds of formulae (B)-(F):

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a), R^(8b), R^(8c),R^(8d), R^(10a), R^(10b), R¹¹, R¹², X⁷, X⁸, X⁹, X¹⁰, Q, m, and q are asdefined for formula (A); p is 1 or 2; or a salt or solvate thereof.

In one variation, compounds of the formula (F) are provided where atleast one of R^(8(a-d)) is a substituted C₁-C₈ alkyl where the C₁-C₈alkyl is substituted with a carbonylalkoxy, carboxyl or acylaminomoiety.

In another variation of formula (F), at least one R^(3a) and R^(3b) isaryl. In a particular variation of formula (F), at least one of R^(3a)and R^(3b) is phenyl.

In any one of the variations of compounds of the formulae herein, suchas compounds of the formulae (I) or (A)-(F), all stereoisomers areintended. For example, the ring bearing the R¹ group of the compound informula (D) can be either

Compositions comprising a single stereoisomer or mixtures of more thanone stereoisomer are also intended. Compositions comprising a mixture ofstereoisomers in any ratio are embraced, including mixtures of two ormore stereochemical forms of a compound of the invention in any ratio,such that racemic, non-racemic, enantioenriched and scalemic mixtures ofa compound are embraced.

In one variation, the compound is of any of the foregoing formulae, suchas any of formulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), wherein,where applicable, R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. Inanother variation, the compound is of any of the foregoing formulae,where R¹ is substituted or unsubstituted C₁-C₈ alkyl or acyl. In afurther variation, the compound is of any of the foregoing formulae,where R¹ is unsubstituted C₁-C₈ alkyl. Where applicable, any variationof the formulae detailed herein may in additional variations be furtherdefined by the R¹ moieties of this paragraph

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where X⁷, X⁸,X⁹ and X¹⁰ are taken together to provide an aromatic moiety selectedfrom the following structures:

where each R⁴ is as defined for formula (I) or (A); or in a particularvariation, where each R⁴ is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino oracyl; or in still a further variation, where R⁴ is independently halo,unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl. In another variation,each R⁴ is independently halo or an unsubstituted C₁-C₈ alkyl. In oneembodiment, the aromatic moiety is substituted is a single R⁴ group,which in one variation is halo or unsubstituted C₁-C₈ alkyl. In one suchvariation, the foregoing rings have (R⁴)₀ substituents, such that thataromatic moiety is unsubstituted and contains no R⁴ groups.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where X⁷, X⁸,X⁹ and X¹⁰ are taken together to provide an aromatic moiety selectedfrom the following structures:

where each R⁴ is as defined for formula (I); or in a particularvariation, where each R⁴ is independently alkyl, perhaloalkyl or halo orin an even more particular variation, where each R⁴ is independentlymethyl, trifluoromethyl, chloro or fluoro. In one embodiment, thearomatic moiety is substituted with a single R⁴ group, which in onevariation is halo or unsubstituted C₁-C₈ alkyl. In one such variation,the foregoing rings have (R⁴)₀ substituents, such that that aromaticmoiety is unsubstituted and contains no R⁴ groups.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where X⁷, X⁸,X⁹ and X¹⁰ are taken together provide an aromatic moiety selected fromthe following structures:

wherein R⁴ is as defined in formula (I), or in a particular variation,where R⁴ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁴ is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄perhaloalkyl. In another variation, R⁴ is halo or unsubstituted C₁-C₈alkyl.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where X⁷, X⁸,X⁹ and X¹⁰ are taken together to provide an aromatic moiety selectedfrom the following structures:

wherein R⁴ is as defined in formula (I) or in any particular variationherein, such as when each R⁴ is independently alkyl or halo or in aneven more particular variation, where each R⁴ is independently methyl,chloro, iodo or fluoro. In one variation, R⁴ is iodo. In anothervariation, R⁴ is chloro. When X⁷, X⁸, X⁹ and X¹⁰ are taken together toform a benzene ring, R⁴ may be positioned at any available carbon atomand each such variation is provided here with any R⁴ detailed herein,including but not limited to when R⁴ is a halo such as chloro, iodo orfluoro.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where X⁷, X⁸,X⁹ and X¹⁰ are taken together provide an aromatic moiety selected fromthe following structures:

Any formula detailed herein, where applicable, may in one variation haveX⁷, X⁸, X⁹ and X¹⁰ taken together to provide an aromatic moiety detailedherein above. It is understood that by “where applicable” it is intendedthat in one variation such X⁷, X⁸, X⁹ and X¹⁰ groups are taken togetherto provide a moiety hereinabove if the formula encompasses such astructure. For example, if a given formula does not encompass structureswherein X⁷, X⁸, X⁹ and X¹⁰ groups are taken together provide a pyridylmoiety, then a pyridyl moiety as detailed hereinabove is not applicableto that particular formula, but remains applicable to formulae that doencompass structures where X⁷, X⁸, X⁹ and X¹⁰ groups are taken togetherprovide a pyridyl moiety.

In another embodiment, a compound of the invention is of the formula(I), wherein X⁷—X¹⁰ are as defined in formula (I) or as detailed in anyvariation herein, where R¹ is H, substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl. In afurther embodiment, a compound of the invention is of the formula (I),wherein X⁷—X¹⁰ are as defined in formula (I) or as detailed in anyvariation herein, where R¹ is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl or substituted or unsubstituted aryl. In a particularvariation, a compound of the invention is of the formula (I), whereinX⁷—X¹⁰ are as defined in formula (I) or as detailed in any variationherein, where R¹ is methyl, ethyl, cyclopropyl, propylate,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where each R⁴is independently H, halo, substituted or unsubstituted C₁-C₈ alkyl,C₁-C₈ perhaloalkyl, substituted or unsubstituted heterocyclyl or asubstituted or unsubstituted aryl. In yet another variation, a compoundof the invention is of formulae (I)-(VI), (Ia)-(h), (A)-(F) and(A-1)-(A-4), or any variation of the foregoing detailed herein, whereeach R⁴ is independently H or a substituted or unsubstituted C₁-C₈alkyl. In still another variation, a compound of the invention is offormulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variationof the foregoing detailed herein, where each R⁴ is H. The invention alsoembraces compounds of formulae (I)-(VI), (Ia)-(h), (A)-(F) and(A-1)-(A-4), or any variation of the foregoing detailed herein, whereeach R⁴ is independently H, halo, unsubstituted C₁-C₄ alkyl, C₁-C₄perhaloalkyl or a substituted or unsubstituted aryl. The inventionfurther embraces compounds of formulae (I)-(VI), (Ia)-(h), (A) -(F) and(A-1)-(A-4), or any variation of the foregoing detailed herein, whereeach R⁴ is independently H, halo, methyl, perfluoromethyl orcyclopropyl.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) are taken togetherto form a moiety selected from the group consisting of the structures:

In certain embodiments, compounds of formulae detailed herein areprovided where R¹ is selected from the following moieties:

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where m, n, q,R^(8a), R^(8b), R^(8C), R^(8d), R^(8e), R^(8f), R¹¹ and R¹², if presentand where applicable, are taken together to form a moiety selected fromthe group consisting of the structures:

When the above structures are applied to the formulae herein, such asformulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4) or any variationthereof, it is understood that q, m, n, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) where applicable are taken together to form theforegoing moieties, including but not limited to, the structures of thisparagraph. Likewise, any formula detailed herein, where applicable, mayin one variation have q, m, n, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) if present, taken together to form a moiety as detailedherein above, including but not limited to, the structures of thisparagraph. It is understood that by “where applicable” it is intendedthat in one variation such q, m, n, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) groups, if present, are taken together to provide amoiety hereinabove if the formula encompasses such a structure. Forexample, if a given formula does not encompass structures wherein q, m,n, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) groups, if present,are taken together to provide a —CH₂CH₂— moiety, then a —CH₂CH₂— moietyas detailed hereinabove is not applicable to that particular formula,but remains applicable to formulae that do encompass structures where q,m, n, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) groups, ifpresent, are taken together to provide a —CH₂CH₂— moiety.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where R^(8c),R^(8d) and the carbon to which they are attached are taken together withR^(8e), R^(8f) and the carbon to which they are attached or R^(8a),R^(8b) and the carbon to which they are attached to form a moietyselected from the group consisting of the structures, each of which maybe optionally substituted, where each R⁸ is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, which may be but is not limited to a substituted orunsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl,furanyl, pyrrolyl or thiophenyl group. In one variation, a compound ofthe invention is of formulae (I)-(VI), (Ia)-(h), (A)-(F) and(A-1)-(A-4), or any variation of the foregoing detailed herein, where Qis a substituted or unsubstituted phenyl or pyridyl group. In aparticular variation, Q is a phenyl or pyridyl group substituted with atleast one methyl group. In another variation, a compound of theinvention is of formulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), orany variation of the foregoing detailed herein, where Q is a pyridyl,phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl orthiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In still anothervariation, a compound of the invention is of formulae (I)-(VI),(Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of the foregoingdetailed herein, where Q is a substituted or unsubstituted C₃-C₈cycloalkyl or a substituted or unsubstituted heterocyclyl. In yetanother variation, a compound of the invention is of formulae (I)-(VI),(Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of the foregoingdetailed herein, where Q is a substituted or unsubstituted pyridyl,phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group.In a particular variation, Q is a pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with atleast one methyl or halo group. In one variation, a compound of theinvention is of formulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), orany variation of the foregoing detailed herein, where Q is anunsubstituted C₃-C₈ cycloalkyl or an unsubstituted heterocyclyl. Inanother variation, a compound of the invention is of formulae (I)-(VI),(Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of the foregoingdetailed herein, where Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. In yet another variation, a compound of the invention is offormulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variationof the foregoing detailed herein, where Q is a substituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety substituted with at least one carbonyl, hydroxymethyl, methyl orhydroxyl group.

In still another variation, a compound of the invention is of theformulae or any variation of the foregoing detailed herein, where Q is amoiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that Q either contains no R⁹ functionality ora moiety of the formula N—R⁹.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that Q either contains no R⁹ functionality ora moiety of the formula N—R⁹.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

wherein each R⁹ is independently alkyl, perhaloalkyl or halo.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

wherein R⁹ is connected to Q ortho or para to the position at which Q isconnected to the carbon bearing R^(8e) and R^(8f). In a particularvariation, Q is a structure of the formula:

and R⁹ is connected to Q para to the position at which Q is connected tothe carbon bearing R^(8e) and R^(8f). In another particular variation, Qis a structure of the formula:

where each R⁹ is independently alkyl, perhaloalkyl or halo.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety of the structure:

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q isselected from the structures:

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀ such that Q either contains no R⁹ functionality or a moiety of theformula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is amoiety selected from the structures:

In yet another variation, a compound is of any formula detailed hereinand, where applicable, Q is

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is asubstituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino moiety. In a particularvariation, Q is an unsubstituted amino. In another variation, Q issubstituted amino of the formula —N(C₁-C₈ alkyl)₂ such as the moiety—N(Me)₂ or —N(CH₃)(CH₂CH₃). In another variation, Q is a substitutedamino of the formula —N(H)(cycloalkyl or substituted cycloalkyl), suchas a moiety of the formula:

In another variation, Q is a substituted amino of the formula —N(H)(arylor substituted aryl), such as a moiety of the formula:

In a particular variation, Q is an amino or substituted amino and R^(8e)and R^(8f) are taken together to form a carbonyl moiety. In yet anothervariation, Q is an acylamino moiety. In still another variation, Q is anacylamino moiety and R^(8e) and R^(8f) are both hydrogen.

In another variation, Q is an alkoxy group of the formula —O—C₁-C₈alkyl, such as the moiety —O—CH₂CH₃. In yet another variation, Q is analkoxy group and R^(8e) and R^(8f) are taken together to form a carbonylmoiety. In still a further variation, Q is a carbonylalkoxy moiety. Inyet another variation, Q is a carbonylalkoxy moiety and R^(8e) andR^(8f) are both hydrogen.

In still another variation, Q is an acyloxy, aminocarbonylalkoxy oracylamino moiety. In one variation, Q is an acyloxy, aminocarbonylalkoxyor acylamino moiety and R^(8e) and R^(8f) are both hydrogen.

The invention also embraces compounds according to any formulae detailedherein, such formulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), orany variation of the foregoing, where applicable, in one variation Q isan aminoacyl moiety. In one variation, Q is an aminoacyl group where atleast one of R_(a) and R_(b) is H, such as when Q is of the formula—NHC(O)R_(b). In one variation, Q is an aminoacyl moiety selected fromthe group consisting of: —NHC(O) -heterocyclyl, —NHC(O)-substitutedheterocyclyl, —NHC(O)-alkyl, —NHC(O)-cycloalkyl, —NHC(O)-alkaryl and—NHC(O)-substituted aryl. In another variation, Q is an aminoacyl moietyselected from the group consisting of: —NHC(O)—C₅-C₇ heterocyclyl,—NHC(O)—C₁-C₆ alkyl, —NHC(O)—C₃-C₇ cycloalkyl, —NHC(O)—C₁-C₃ alkaryl and—NHC(O)-substituted phenyl.

Also embraced are compounds according to any formulae detailed herein,such formulae (I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or anyvariation of the foregoing, where applicable, in one variation Q isacyloxy.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is acarbonylalkoxy moiety. In one variation, Q is a carbonylalkoxy moiety ofthe formula —C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl.In one variation, Q is carbonylalkoxy moiety of the formula—C(O)—O—C₁-C₆ alkyl. In a particular variation, Q is a carbonylalkoxymoiety of the formula —C(O)—O—C₂H₅. In one variation, Q is acarbonylalkoxy moiety selected from the group consisting of:—C(O)—O—C₁-C₁₀ alkyl, —C(O)—O—C₁-C₃ alkaryl, —C(O)—O—C₁-C₃ substitutedalkyl and —C(O)—OH. In another variation, Q is —C(O)—O—C₁-C₆ alkyl.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is anaminocarbonylalkoxy moiety. In one variation, Q is anaminocarbonylalkoxy moiety of the formula —NHC(O)—O—R_(b). In anothervariation, Q is an aminocarbonylalkoxy moiety of the formula—NHC(O)—O—R_(b) where R_(b) is a substituted alkyl group. In aparticular variation, Q is a moiety of the formula—NH—C(O)—O—CH₂—C(Cl)₃.

Compounds according to any formulae detailed herein, such formulae(I)-(VI), (Ia)-(h), (A)-(F) and (A-1)-(A-4), or any variation of theforegoing, where applicable, in one variation is provided where Q is anacylamino moiety. In one variation, Q is an acylamino group where atleast one of R_(a) and R_(b) is H, such as when Q is of the formula—C(O)N(H)(R_(b)). In another variation, Q is an acylamino group whereboth R_(a) and R_(b) alkyl. In one variation, Q is an acylamino moietyselected from the group consisting of: —C(O)N(H)(alkyl), —C(O)N(alkyl)₂,—C(O)N(H)(alkaryl) and —C(O)N(H)(aryl). In another variation, Q is anacylamino moiety selected from the group consisting of: —C(O)N(H)₂,—C(O)—N(H)(C₁-C₈ alkyl), —C(O)N(C₁-C₆ alkyl)₂ and —C(O)N(H)(C₁-C₃alkaryl).

Any formula detailed herein, where applicable, may in one variation haveas Q the moieties detailed herein above. It is understood that by “whereapplicable” it is intended that such Q moieties be a variation if theformula encompasses such a structure. For example, if a given formuladoes not encompass structures wherein Q is a phenyl moiety, then aphenyl moiety is not applicable to that particular formula, but remainsapplicable to formulae that do encompass structures where Q is a phenylmoiety.

In another variation, a compound of the invention is of formulae(I)-(VI), or any variation of the foregoing detailed herein, where q, m,n, Q and R^(8a)—R^(8f) are taken together to form a moiety of thestructure:

In another variation, a compound of the invention is of formulae(I)-(VI), or any applicable variation of the foregoing detailed herein,where q, m, and n, Q, R^(8(a-f)), R¹¹ and R¹² where applicable are takentogether to form a moiety of the structure:

In another variation, any formula detailed herein, where applicable, mayin one variation have q, m, and n, Q, R^(8(a-f)), R¹¹ and R¹² whereapplicable taken together to form a moiety of the structure:

Examples of compounds according to the invention are depicted inTable 1. The compounds depicted may be present as salts even if saltsare not depicted and it is understood that the invention embraces allsalts and solvates of the compounds depicted here, as well as thenon-salt and non-solvate form of the compound, as is well understood bythe skilled artisan.

TABLE 1 Respresentative Compounds According to the Invention. CompoundNo. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

Compounds of the invention, such as compounds of the formula (I), may beused in a method of modulating a histamine receptor.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. Taking compound 1 as an example, acomposition of substantially pure compound 1 intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than compound 1 or a salt thereof. In one variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains no more than 25% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 20%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 10% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 5% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 0.5% impurity.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g., α1D,α2A and α2B), inhibition of binding of a ligand to a serotonin receptor(e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and 5-HT₇), inhibition of binding ofa ligand to a dopamine receptor (e.g., D_(2L)), and inhibition ofbinding of a ligand to a histamine receptor (e.g., H₁, H₂ and H₃);agonist/antagonist activity to a serotonin receptor (e.g., 5-HT_(2A),5-HT₆); agonist/antagonist activity to a dopamine receptor (e.g.,D_(2L), D_(2S)); agonist/antagonist activity to a histamine receptor(e.g., H₁); activity in a neurite outgrowth assay; efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction; efficacy in a preclinical model ofattention/impulsivity and executive function and efficacy in apreclinical model of schizophrenia.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85% and about 95% or between about90% and about 100% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by at least about 80%±20% asdetermined in an assay known in the art.

In one variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailed herein(e.g. α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇,D_(2L), H₁, H₂, H₃). In one variation, a compound of the inventioninhibits binding of a ligand to at least one receptor and as many aseleven as detailed herein (e.g., α_(1D), α_(2A), α_(2B), 5-HT_(2A),5-HT_(2C), 5-HT₆, 5-HT₇, D₂, H₁, H₂, H₃). In one variation, a compoundof the invention inhibits binding of a ligand to at least one and asmany as eleven receptors detailed herein and further displays agonist orantagonist activity to one or more receptors detailed herein (e.g.,serotonin receptor 5-HT_(2A), serotonin receptor 5-HT₆, dopaminereceptor D_(2L), and dopamine receptor D_(2S), histamine receptor H₁) asmeasured in the assays described herein. In one variation, agonistresponse of serotonin receptor 5-HT_(2A) is inhibited by compounds ofthe invention by at least about any one of 50%, 50%, 70%, 80%, 90%,100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assaysuch as the assay described herein.

In one variation, a compound of the invention displays the abovedescribed neurotransmitter receptor binding profile i.e. inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein and further stimulates neurite outgrowth, e.g. asmeasured by the assays described herein. In one variation, a compound ofthe invention shows activity in neurite outgrowth assays using primaryneurons in culture. In another variation, a compound of the inventionhas activity comparable in magnitude to that of naturally occurringprototypical neurotrophic proteins such as brain derived neurotrophicfactor (BDNF) and nerve growth factor (NGF). Notably, neurite outgrowthplays a critical part of new synaptogenesis, which is beneficial for thetreatment of neuronal disorders. In one variation, neuronal disordersinclude ADHD. In one variation, neurite outgrowth is observed with apotency of about 1 μM as measured in a suitable assay known in the artsuch as the assays described herein. In another variation, neuriteoutgrowth is observed with a potency of about 500 nM. In a furthervariation, neurite outgrowth is observed with a potency of about 50 nM.In another variation, neurite outgrowth is observed with a potency ofabout 5 nM.

In another variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein and/or display the above described neurotransmitter receptorbinding profile and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,and in preclinical models of attention/impulsivity and executivefunction, i.e. shows pro-cognitive effects in a preclinical model ofmemory dysfunction. In one variation, a compound of the invention iseffective in a preclinical model of memory dysfunction associated withcholinergic hypofunction. As H₁ antagonism may contribute to sedation,weight gain and reduced cognition, low affinity (less than about 80%inhibition of binding of Pyrilamine at 1 μM in the assay describedherein) for this receptor may be associated with pro-cognitive effectsand a more desirable side effect profile. Furthermore, compounds of theinvention with increased potency as a 5-HT₆ antagonist may havecognition-enhancing effects as serotonin acting through this receptormay impair memory.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction i.e.shows pro-cognitive effects in a preclinical model of memorydysfunction, and in preclinical models of attention/impulsivity andexecutive function, and further displays agonist or antagonist activityto one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction, i.e.shows pro-cognitive effects in a preclinical model of memorydysfunction, and in preclinical models of attention/impulsivity andexecutive function, and in preclinical models of attention/impulsivityand executive function, and further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction i.e.shows pro-cognitive effects in a preclinical model of memorydysfunction, and in preclinical models of attention/impulsivity andexecutive function, and in preclinical models of attention/impulsivityand executive function, further displays agonist or antagonist activityto one or more receptor detailed herein and further stimulates neuriteoutgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furtherpossesses anti-psychotic effects as measured in a preclinical model ofschizophrenia, i.e., shows efficacy in a preclinical model ofschizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further displaysagonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment and in preclinical modelsof attention/impulsivity and executive function, and further showsefficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed hereinand further shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction such as enhancementof memory retention and reduction of memory impairment and inpreclinical models of attention/impulsivity and executive function.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment and in preclinical models of attention/impulsivity andexecutive function.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein, further stimulates neurite outgrowth andfurther shows efficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed herein,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment and in preclinical models ofattention/impulsivity and executive function.

In another variation, a compound of the invention stimulates neuriteoutgrowth. In another variation, a compound of the invention showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In another variation, a compound of the inventionstimulates neurite outgrowth and further shows efficacy in a preclinicalmodel of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment and in preclinical models ofattention/impulsivity and executive function. In another variation, acompound of the invention shows efficacy in a preclinical model ofschizophrenia, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment and in preclinical modelsof attention/impulsivity and executive function.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α_(1D), α_(2A), α_(2B) and inhibit binding of aligand to serotonin receptor 5-HT₆. In another variation, compounds ofthe invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and to any one ormore of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A) and5-HT_(2C). In another variation, compounds of the invention inhibitbinding of a ligand to adrenergic receptors α_(1D), α_(2A), α_(2B), toserotonin receptor 5-HT₆ and to any one or more of the followingreceptors: serotonin receptor 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and furthershow weak inhibition of binding of a ligand to histamine receptor H₁and/or H₂. In one variation, compounds of the invention that alsodisplay strong inhibition of binding of a ligand to the serotoninreceptor 5-HT₇ are particularly desired. In another variation, compoundsof the invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and further showweak inhibition of binding of a ligand to histamine receptor H₁ and/orH₂. Weak inhibition of binding of a ligand to the histamine H₁ receptoris permitted as agonists of this receptor have been implicated instimulating memory as well as weight gain. In one variation, binding tohistamine receptor H₁ is inhibited by less than about 80%. In anothervariation, binding of a ligand to histamine receptor H₁ is inhibited byless than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined bya suitable assay known in the art such as the assays described herein.

In another variation, compounds of the invention inhibit binding of aligand to a dopamine receptor D₂. In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D_(2L). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D₂ and to serotonin receptor 5-HT_(2A). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D_(2L) and to serotonin receptor 5-HT_(2A).In another variation, compounds of the invention inhibit binding of aligand to histamine receptor H₁. In certain aspects, compounds of theinvention further show one or more of the following properties: stronginhibition of binding of a ligand to the serotonin 5-HT₇ receptor,strong inhibition of binding of a ligand to the serotonin 5-HT_(2A)receptor, strong inhibition of binding of a ligand to the serotonin5-HT_(2C) receptor, weak inhibition of binding of a ligand to thehistamine H₁ receptor, weak inhibition of binding of ligands to thehistamine H₂ receptor, and antagonist activity to serotonin receptor5-HT_(2A).

In one variation, compounds of the invention show any of the receptorbinding aspects detailed herein and further display agonist/antagonistactivity to one or more of the following receptors: serotonin receptor5-HT_(2A), serotonin receptor 5-HT₆, dopamine receptor D_(2L), dopaminereceptor D_(2S) and histamine receptor H₁. In one variation, compoundsof the invention show any of the receptor binding aspects detailedherein and further stimulate neurite outgrowth. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment and in preclinical models of attention/impulsivity andexecutive function. In one variation, compounds of the invention showany of the receptor binding aspects detailed herein and further showefficacy in a preclinical model of schizophrenia. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in any one or more ofagonist/antagonist assays (e.g., to serotonin receptor 5-HT_(2A), 5-HT₆,dopamine receptor D_(2L), dopamine receptor D_(2S) and histaminereceptor H₁), neurite outgrowth, a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction and apreclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligandto adrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆and a dopamine receptor D₂ by at least about 80% as determined in asuitable assay known in the art such as the assays described herein. Insome aspects, compounds of the invention inhibit binding of a ligand toadrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆and dopamine receptor D_(2L) by at least about 80% as determined in asuitable assay known in the art such as the assays described herein. Inone variation binding is inhibited by at least about 80% as measured ina suitable assay such as the assays described herein. In one variationbinding is inhibited by at least about 80% as measured in a suitableassay such as the assays described herein. In one variation, binding ofa ligand to a receptor is inhibited by greater than about any one of80%, 85%, 90%, 95%, 100%, or between about 85% and about 95%, or betweenabout 90% and about 100% as determined in a suitable assay known in theart such as the assays described herein.

In some aspects, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. In one variation, a compound of the invention has bindingprofiles similar to compounds with antipsychotic activity. In anothervariation, a compound of the invention is effective in a preclinicalmodel of schizophrenia. In addition, compounds of the invention mightpossess the cognitive enhancing properties of dimebon and thus add tothe beneficial pharmacology profile of these antipsychotic molecules. Inone variation, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show pro-cognitiveeffects in a preclinical model of memory dysfunction. In anothervariation, compounds of the invention display the above describedneurotransmitter receptor binding profile and do not show pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory.

In one variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory. In a further variation, compounds of the invention possessanti-psychotic effects in a preclinical model of schizophrenia. In afurther variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory, and further possess anti-psychotic effects in a preclinicalmodel of schizophrenia.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersin individuals, such as humans. In one aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a cognitive disorder. In one variation, cognitivedisorder as used herein includes and intends disorders that contain acognitive component, such as psychotic disorders (e.g., schizophrenia)containing a cognitive component (e.g., CIAS). In one variation,cognitive disorder includes ADHD. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of a psychotic disorder. In one variation,psychotic disorder as used herein includes and intends disorders thatcontain a psychotic component, for example cognitive disorders (e.g.,Alzheimer's disease) that contain a psychotic component (e.g., psychosisof Alzheimer's Disease or dementia). In one variation, methods ofimproving at least one cognitive and/or psychotic symptom associatedwith schizophrenia are provided. In one aspect, methods of improvingcognition in an individual who has or is suspected of having CIAS areprovided. In a particular aspect, methods of treating schizophrenia areprovided wherein the treatment provides for an improvement in one ormore negative symptom and/or one or more positive symptom and/or one ormore disorganized symptom of schizophrenia. In yet another aspect, thecompounds described herein may be used to treat, prevent, delay theonset and/or delay the development of a neurotransmitter-mediateddisorders disorder. In one aspect, a neurotransmitter-mediated disorderincludes ADHD. In one embodiment, the neurotransmitter-mediated disorderincludes spinal cord injury, diabetic neuropathy, allergic diseases(including food allergies) and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Inanother variation, the neurotransmitter-mediated disorder includesspinal cord injury, diabetic neuropathy, fibromyalgia and allergicdiseases (including food allergies). In still another embodiment, theneurotransmitter-mediated disorder includes Alzheimer's disease,Parkinson's disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, multiple sclerosis, stroke and traumatic brain injury. Inyet another embodiment, the neurotransmitter-mediated disorder includesschizophrenia, anxiety, bipolar disorders, psychosis, depression, andADHD. In one variation, depression as used herein includes and intendstreatment-resistant depression, depression related to a psychoticdisorder, or depression related to a bipolar disorder. In anotheraspect, the compounds described herein may be used to treat, prevent,delay the onset and/or delay the development of a neuronal disorder. Inone aspect, the compounds described herein may also be used to treat,prevent, delay the onset and/or delay the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects. In a particular variation, amethod of treating schizophrenia is provided, wherein the treatmentprovides an improvement in at least one cognitive function, such as animprovement in a cognitive function in an individual who has or issuspected of having CIAS. In a further variation, a method of treatingschizophrenia is provided wherein the method reduces psychotic effectsassociated with schizophrenia. In one embodiment, a method of treatingschizophrenia is provided wherein the method improves the negativesymptoms of schizophrenia in an individual in need thereof. In oneembodiment, a method of treating schizophrenia is provided wherein themethod improves the positive symptoms of schizophrenia in an individualin need thereof. In a further variation, a method of treatingschizophrenia is provided wherein the method both improves cognitivefunction and reduces psychotic effects in an individual in need thereof.A method of improving one or more negative, positive and disorganizedsymptoms of schizophrenia is also provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In one variation, a method of improving at least one negative symptom ofschizophrenia is provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In anothervariation, a method of improving at least one negative and at least onepositive symptom of schizophrenia is provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In yet another variation, a method of improving at least one negativeand at least one disorganized symptom of schizophrenia is also provided,where the method entails administering a compound as detailed herein, ora pharmaceutically acceptable salt thereof, to an individual in need ofsuch improvement. In still another variation, a method of improving atleast one positive and at least one disorganized symptom ofschizophrenia is also provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In still afurther variation, a method of improving at least one negative, at leastone positive and at least one disorganized symptom of schizophrenia isprovided, where the method entails administering a compound as detailedherein, or a pharmaceutically acceptable salt thereof, to an individualin need of such improvement.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-Mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆, 5-HT₇,histamine receptor H₁ and/or H₂ is expected to be or is beneficial forthe cognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α_(1D), α_(2A), α_(2B) and a serotonin receptor5-HT₆ receptor is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of adrenergicreceptor α_(1D), α_(2A), α_(2B), and a serotonin receptor 5-HT₆ receptorand modulation of one or more of the following receptors serotonin5-HT₇, 5-HT_(2A), 5-HT_(2C) and histamine H₁ and H₂ is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of dopamine receptor D_(2L) is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. Incertain variations, modulation of a dopamine D_(2L) receptor andserotonin receptor 5-HT_(2A) is expected to be or is beneficial for thecognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders are treated, prevented and/or their onset ordevelopment is delayed by administering a compound of the invention.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆,5-HT₇, histamine receptor H₁ and/or H₂ is desirable or expected to bedesirable to improve cognitive functions. In some variations modulationof α_(1D), α_(2A), α_(2B) adrenergic receptors and a serotonin 5-HT₆receptor is desirable or expected to be desirable to improve cognitivefunctions. In some variations, modulation of α_(1D), α_(2A), α_(2B)adrenergic receptors and serotonin receptor 5-HT₆ and modulation of oneor more of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A),5-HT_(2C) and histamine receptor H₁ and H₂, is desirable or expected tobe desirable to improve cognitive functions. In another aspect, theinvention encompasses methods to reduce psychotic effects byadministering a compound of the invention to an individual in needthereof. In some embodiments, modulation of a dopamine D₂ receptor isexpected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D₂ receptor and a serotonin5-HT_(2A) receptor is expected to be or is desirable to reduce psychoticeffects. In some embodiments, modulation of a dopamine D_(2L) receptoris expected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor and a serotonin5-HT_(2A) receptor is expected to be or is desirable to reduce psychoticeffects. In some variations, a compound of the invention is administeredto an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ and 5-HT₇ receptor. In some variations, theaminergic G protein-coupled receptor is a α_(1D), α_(2A), α_(2B)adrenergic receptor, a serotonin 5-HT₆ and one or more of the followingreceptors: serotonin 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and histamine H₁ andH₂ receptor. In some variations, the aminergic G protein-coupledreceptor is a dopamine D₂ receptor. In some variations, the aminergic Gprotein-coupled receptor is a dopamine D_(2L) receptor. In somevariations, the aminergic G protein-coupled receptor is a dopamine D₂receptor and a serotonin 5-HT_(2A) receptor. In some variations, theaminergic G protein-coupled receptor is a dopamine D_(2L) receptor and aserotonin 5-HT_(2A) receptor. In some variations, the aminergic Gprotein-coupled receptor is a histamine H₁ receptor.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to formulae (I)-(VI), (Ia)-(h),(A)-(F) and (A-1) -(A-4) or a variation thereof unless otherwiseindicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

By way of example only, using suitable methods such as those detailedherein, compounds of the formula (D) may be resolved to providecompounds of the formulae (Da) and (Db):

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor(Rf).

General methods of preparing compounds according to the invention aredepicted in exemplified methods below. Other compounds of the inventionmay be prepared by similar methods. Synthetic methods to provide similarintermediates have also been described in, for example, PCT PatentApplication Nos. PCT/US2008/081390, PCT/US2009/032065, PCT/US2009/038142and PCT/US2009/038138; the experimental details of each of which areincorporated herein by reference.

Appropriately substituted piperidin-4-ones (G-1 to G-8), as utilized inGeneral Methods 1 and 3, are exemplified by the general structuresbelow. Preparation of such substituted piperidin-4-ones will be familiarto those skilled in the art, and literature routes thereto have beendescribed by, for example, King et al., [J. Med. Chem. (1993),36(6):683-689], Howard et al., [Tetrahedron Lett. (1980),21(14):1373-1374], King, F. [Tetrahedron Lett. (1983),24(31):3281-3282], Cordonnier et al., [Tetrahedron Lett. (1994),35(46):8617-8618], Cordero et al., [Tetrahedron Lett. (1995),36(8):1343-1346], and Cava et al., [J. Org. Chem. (1965), 30:3772-3775].

General Method 1-A

As shown in Scheme 1, in general a suitably substituted hydrazine H canbe reacted with an appropriately substituted reagent J to generate asubstituted hydrazine K, where the internal nitrogen on the hydrazine issubstituted, as shown above. The reaction of intermediate K with anappropriately substituted piperidin-4-one G should provide structures ofthe type generally described by structure L.

General Method 1-B

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein Q is aryl,substituted aryl, heteroaryl (five and six membered) and substitutedheteroaryl (five and six membered).

General Method 1-C

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein Q is alkyl,substituted alkyl, substituted or unsubstituted amino, thio, substitutedthio, alkoxy, cycloalkyl and heterocyclic (including 4, 5, 6 and7-membered rings).

General Method 1-D

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein q and m=0, and Q isalkyl, substituted alkyl, substituted or unsubstituted amino, thio,substituted thio, alkoxy, cycloalkyl and heterocyclic (including 4, 5, 6and 7-membered rings).

General Method 1-E

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m=0, q=1, R^(8a)and R^(8b) taken together with the carbon to which it is attached form acarbonyl moiety, R^(8e) and R^(8f) is independently H, hydroxyl or C₁-C₈alkyl; and Q is alkyl, substituted alkyl, substituted or unsubstitutedamino, thio, substituted thio, alkoxy, cycloalkyl and heterocyclic(including 4, 5, 6 and 7-membered rings).

General Method 1-F

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m=0, q=1, R^(8e)and R^(8f) taken together with the carbon to which it is attached form acarbonyl moiety, R^(8a) and R^(8b) is independently H, hydroxyl or C₁-C₈alkyl; and Q is alkyl, substituted alkyl, substituted or unsubstitutedamino, thio, substituted thio, alkoxy, cycloalkyl and heterocyclic(including 4, 5, 6 and 7-membered rings).

General Method 1-G

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m and q=1, R^(8a)and R^(8b) taken together with the carbon to which it is attached form acarbonyl moiety, R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl or C₁-C₈ alkyl; and Q is alkyl, substituted alkyl, substitutedor unsubstituted amino, thio, substituted thio, alkoxy, cycloalkyl andheterocyclic (including 4, 5, 6 and 7-membered rings).

General Method 1-H

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m and q=1, R^(8e)and R^(8f) taken together with the carbon to which it is attached form acarbonyl moiety, R^(8a), R^(8b), R^(8c) and R^(8d) is independently H,hydroxyl or C₁-C₈ alkyl; and Q is alkyl, substituted alkyl, substitutedor unsubstituted amino, thio, substituted thio, alkoxy, cycloalkyl andheterocyclic (including 4, 5, 6 and 7-membered rings).

General Method 1-I

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein q and m=0, and Q isCOOR.

General Method 1-J

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m=0, q=1, and Q isCOOR.

General Method 1-K

Similar synthetic details may be employed for compounds made accordingto General Method 1-A in general methods for synthesis of structures ofthe type generally described by structure L, wherein m and q=1, and Q isCOOR.

General Method 2

Arylhydrazine hydrochloride (1 equiv) is mixed with triethylamine (3equiv) and alkyl halide (1 equiv) at 25° C. The reaction mixture isstirred at RT for 1 h and subsequently heated at 90° C. for 16 h atwhich point the reaction is found complete by TLC and LC-MS. Thereaction mixture is concentrated under reduced pressure, diluted withwater and extracted with EtOAc. The combined organic layer is dried(Na₂SO₄) and concentrated to obtain crude product that is purified bycolumn chromatography (silica gel, 100-200 mesh, eluent: EtOAc-hexanesgradient).

General Method 3

Aryl hydrazine or substituted aryl hydrazine hydrochloride (1 equiv) andappropriate hydrochloride salt of tropinone (1 equiv) are mixed in asuitable solvent such as EtOH and heated at 80-100° C. for 16 h(overnight) after which the solvent is removed in vacuo. The remainingresidue is basified, e.g., with saturated aq. NaHCO₃. The aqueous layeris extracted with DCM or EtOAc and the combined organic layers are driedover Na₂SO₄, and concentrated in vacuo. The resulting crude product ispurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient,and/or by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

General Method 4

A mixture of appropriate carboline derivative with side chaincarboxylate ester (1 equiv) and NaOH (3N, 5 fold w/v) in EtOH (5 foldw/v) is stirred at 50° C. for 3 h after which it is cooled to RT andneutralized with conc. HCl. The solvent is removed under reducedpressure to obtain corresponding crude carboxylic acid. The resultingcrude product is purified by silica gel chromatography (100-200 mesh or230-400 mesh) using MeOH-DCM gradient, by neutral alumina usingEtOAc-hexane gradient, and/or by reverse-phase chromatography (C-18, 500mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

General Method 5

A mixture of appropriate carboline derivative with side chain carboxylicacid (1 equiv) is stirred with appropriate alcohol (1 equiv), EDCI-HCl(1 equiv) and triethylamine (1 equiv) in DCM for 12-16 h. The reactionmixture is evaporated under vacuo to obtain the crude ester that ispurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient,and/or by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

General Method 6A

A mixture of appropriate carboline derivative with side chain carboxylicacid (1 equiv) is stirred with appropriate amine (1 equiv), EDCI (1equiv) and triethylamine (1 equiv) in DCM for 12-16 h. The reactionmixture is evaporated in vacuo to obtain the crude amide that ispurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient,and/or by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

General Method 6B

Appropriate carboxylic acid (1 equiv 0.150 g, 0.472 mmol) is dissolvedin DCM and cooled to 0° C. Oxalyl chloride (1.5 equiv) is addeddrop-wise followed by addition of a catalytic amount ofdimethyl-formamide and the reaction mixture is stirred for 1 h at RT.Excess oxalyl chloride is distilled off under reduced pressure; asolution of appropriate amine (1.1 equiv) in DCM and4-(N,N-dimethylamino)pyridine (1.2 equiv) is added to t his residueunder nitrogen at RT and reaction mixture is stirred for 30 min at RT.The reaction mixture is quenched with water and neutralized with 10%NaHCO₃, extracted with EtOAc (2×10 mL). The combined organic layers aredried over sodium sulfate and concentrated under reduced pressure toprovide the crude product that is purified by silica gel chromatographyand/or reverse phase HPLC.

General Method 7

Carboline derivative (1 equiv), epoxide derivative (4-7.5 equiv) and NaH(3 equiv) are heated in DMF (3 mL/mmol) at 120° C. for 16 h. Thecontents are quenched by MeOH and evaporated to dryness. The resultingcrude product is purified by silica gel chromatography (100-200 mesh or230-400 mesh) using MeOH-DCM gradient, by neutral alumina usingEtOAc-hexane gradient, and/or by reverse-phase chromatography (C-18, 500mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

General Method 8

Appropriate carboline (1 equiv) is dissolved in NMP (0.6 mL/mmol).Powdered KOH (3.5 equiv) is added to this solution, and the reactionmixture is stirred for 10 min at 25° C. Appropriate vinylpyridinederivative (1.1 equiv) is added and the reaction mixture is heated insealed tube at 45° C. for 30 min. The reaction is monitored by LCMS.After this period, the reaction mixture is cooled to 25° C. and dilutedwith saturated aqueous NaCl (5 mL). The product is extracted with EtOAc.The combined organic layer is dried over anhydrous sodium sulfate andevaporated under reduced pressure. The resulting crude product ispurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient,and/or by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

General Method 9

Appropriate carboline (1 equiv) is dissolved in DCM (3 mL/mmol) andcooled to 0° C. Triethylamine (1 equiv) is added followed by appropriateacid chloride. The reaction mixture is slowly allowed to warm to 25° C.and stirred at 25° C. for 24 h. The reaction mixture is quenched byadding saturated aqueous NaHCO₃ and extracted with DCM. The combinedorganic layer is dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The resulting crude product is purified bysilica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCMgradient, by neutral alumina using EtOAc-hexane gradient, and/or byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol. 5 mL).

General Method 10

An appropriate carboline derivative with side chain nitrile (1 equiv) istreated with diisobutylaluminum hydride (3 equiv) in toluene (5 mL/mmol)at 80° C. for 1-2 h. The reaction mixture is cooled to 25° C., quenchedwith water and extracted EtOAc. The combined organic layer is dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresulting crude product is purified by silica gel chromatography(100-200 mesh or 230-400 mesh) using MeOH-DCM gradient, by neutralalumina using EtOAc-hexane gradient, and/or by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

General Method 11

A mixture of appropriate carboline derivative with side chain amine (1equiv) is stirred with appropriate carboxylic acid (1 equiv), EDCI (1equiv) and triethylamine (1 equiv) in DCM for 12-16 h. The reactionmixture is evaporated in vacuo to obtain the crude amide that ispurified by silica gel chromatography (100-200 mesh or 230-400 mesh)using MeOH-DCM gradient, by neutral alumina using EtOAc-hexane gradient,and/or by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile PhaseA=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to80% B in 30 min, injection vol. 5 mL).

General Method 12

A mixture of appropriate carboline derivative with side chaincarboxylate ester (1 equiv) and appropriate amine (10 fold w/v) isheated at 120° C. for 12-18 h after which the reaction mixture isevaporated to dryness and the resulting crude product was purified bysilica gel chromatography (100-200 mesh or 230-400 mesh) using MeOH-DCMgradient, by neutral alumina using EtOAc-hexane gradient, and/or byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol. 5 mL).

General Method 13

An appropriately substituted carboline (0.36 mmol) is dissolved in DMF.To this solution CuI (1 equiv), L-proline (0.02 equiv), K₃PO₄ (2 equiv)are added and the reaction mixture is stirred for 10 min at RT. This isfollowed by dropwise addition of (2-bromovinyl)arene (100 mg, 1.2equiv). The reaction mixture is heated at 80° C. overnight. The DMF isevaporated under reduced pressure and the product is extracted withEtOAc and the organic layer is washed with brine. The organic layer isdried over anhydrous Na2SO4, and concentrated under reduced pressure.The crude compound thus obtained is purified by column chromatography onsilica gel to afford the product. The general method may be modified toreach similar products, e.g., by substituting (2-bromovinyl)arene withlike compounds.

General Method 14

An appropriately substituted carboline derivative (1 equiv) is heated toreflux with 25% aqueous sulfuric acid for 2 h. The reaction mixture iscooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is addeddropwise to the reaction mixture to a pH of 9-10. The reaction mixtureis extracted with EtOAc. The combined organic layer is washed with water(10 mL) followed by brine, dried over sodium sulfate and evaporatedunder vacuum. The crude product is purified by column chromatography onsilica gel (100-200 mesh).

General Method 15A

To a stirred solution of an appropriately substituted carboline (1equiv) and copper sulfate (0.01 equiv) in toluene is added potassiumcarbonate (2 equiv) and 1,10 phenanthroline (0.05 equiv). The reactionmixture is stirred for 5 min at RT. A solution of 1-bromoethynylarene (1equiv) in toluene is added to the reaction mixture. The reaction mixtureis stirred for 2 h at 80° C. Solvent is removed under reduced pressureand the resulting crude product is purified by column chromatography onsilica gel. The general method may be modified to reach similarproducts, e.g., by substituting 1-bromoethynylarene with like compounds.

General Method 15B

An appropriately substituted carboline is added to a solution of sodiumhydride (5 equiv) in THF at 0° C. and the contents are stirred at 0° C.for 30 min. A solution of appropriately substituted alkyl halide (2equiv) in THF is added dropwise to the reaction mixture which andstirred at RT for 3 h. After completion of the reaction, the reactionmixture is quenched with ice cold water and product extracted withEtOAc, washed with water, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude compound. The crude product ispurified to yield the desired product. The general method may bemodified to reach similar products, e.g., by substitutingchloroacetamide with like compounds.

General Method 15C

I. Tetrabutylammonium chloride (0.5 equiv) is dissolved in 50% NaOHfollowed by addition of an appropriately substituted carboline (1equiv). The reaction mixture is stirred for 5 min at RT, and appropriatealkyl halide (1 equiv) is added and stirred at 100° C. for 12 h. Thereaction is quenched with water and extracted in DCM. The combinedorganic layers are dried over sodium sulfate and concentrated undervacuum to yield the crude product which is purified by reverse phasechromatography.

II. An appropriately substituted carboline (1 equiv) and appropriatealkyl halide (1 equiv) is added to a vigorously stirred mixture oftetra-n-butyl ammonium chloride (0.5 equiv) in 50% aq NaOH solution andthe resultant mixture is heated at 60° C. for 6 h. Upon completion (thereaction is monitored by LCMS), the reaction is quenched with andextracted with DCM, the combined organic layers are separated, driedover Na₂SO₄ and concentrated, and the resultant crude is purified byreverse-phase chromatography.

III. An appropriately substituted carboline (1 equiv) is added to asolution of tetra n-butyl ammonium chloride (0.5 equiv) in 50% aq NaOHand stirred for 30 min. An appropriate alkyl halide (1 equiv) is addedand the reaction mixture is heated at 60° C. for 15 h. The progress ofthe reaction is monitored by LCMS and TLC. After complete reaction, thereaction mixture is quenched with water and extracted with EtOAc. Thecombined organic layers are dried over sodium sulfate and concentratedunder reduced pressure and the resultant crude product is purified bychromatography.

General Methods for HPLC Analysis

Method-1

-   Column: YMC ODS-A 150 mm×4.6 mm×5μ, ID: E-AC-1/06/COL/013-   Mobile Phase: A: 0.05% TFA in Water/B: 0.05% TFA in Acetonitrile-   Inj. Vol: 10 μL, Col. Temp.: 30° C., Flow rate: 1.2 mL/min-   Gradient: 10% B to 80% B in 5 min, Hold for 2 min, 7.01-10 min 10% B    Method-2-   Column: YMC ODS-A 150 mm×4.6 mm×5μ, ID: E-AC-1/06/COL/013-   Mobile Phase: A: 0.05% TFA in Water/B: 0.05% TFA in Acetonitrile-   Inj. Vol: 10 μL, Col. Temp.: 30° C., Flow rate: 1.2 mL/min-   Gradient: 50% B to 100% B in 5 min, Hold for 2 min, 7.01-10 min 50%    B    Method-3-   Column: YMC ODS-A 150 mm×4.6 mm×5μ, ID: E-AC-1/06/COL/013-   Mobile Phase: A: 0.05% TFA in Water/B: 0.05% TFA in Acetonitrile-   Inj. Vol: 10 μL, Col. Temp.: 30° C., Flow rate: 1.4 mL/min-   Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below.

The following Examples are provided to illustrate but not limit theinvention.

All references disclosed herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Preparation of7-(4-fluorophenethyl)-10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole[Compound No. 1]

A mixture of7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole(non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) wereheated at 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6mL of EtOH for 18 h. The mixture was brought to RT followed by dilutionwith EtOAc (40 mL), washed with water (2×10 mL), and once with brine,then dried over sodium sulfate and evaporated under reduced pressure.The crude product was purified by column chromatography over230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%).The product was further purified by reverse phase HPLC.

Column: ZORBAX SB C18, 4.6×250 mm, 5μ, retention time (min): 9.71,purity: 95.20%;

¹H NMR (DMSO, TFA salt) δ (ppm): 7.50 (m, 1H), 7.40 (m, 3H), 7.12 (m,3H), 5.0 (m, 1H), 3.80 (m, 2H), 3.60 (m, 2H), 3.55 (m, 2H), 3.45 (m,1H), 3.38-3.20 (m, 2H), 3.10 (m, 2H), 2.70 (m, 1H), 2.25 (m, 2H).

Example 2 Preparation of10-(4-fluorophenethyl)-7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole [Compound No. 2]

A mixture of7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole(non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) wereheated to 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6mL of EtOH for 18 h. The mixture was brought to RT followed by dilutionwith EtOAc (40 mL), washed with water (2×10 mL), then with brine, driedover sodium sulfate and evaporated under reduced pressure. The crudeproduct was purified by column chromatography over 230-400-mesh silicagel using a gradient of MeOH in EtOAc (0 to 50%). The product wasfurther purified by reverse phase HPLC.

Column: ZORBAX SB C18, 4.6×250 mm, 5 μm, retention time (min): 9.47,purity: 80.24%;

¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.38 (s, 1H), 7.30 (d, 1H), 7.10 (m,3H), 6.90 (m, 2H), 5.05 (d, 1H), 4.40 (m, 1H), 4.20 (m, 2H), 3.50 (m,1H), 3.20 (m, 2H), 3.10 (m, 2H), 3.0 (m, 2H), 2.5-2.3 (m, 3H), 2.0 (m,1H).

Example 3 Preparation of(E)-10-(2-(4-fluorophenyl)prop-1-enyl)-7-methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole[Compound No. 3]

7-Methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (45 mg,0.198 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (3.76 mg,0.0198 mmol), L-proline (2.1 mg, 0.0398 mmol) and K₃PO₄ (71 mg, 0.396mmol) were added and the reaction mixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (51 mg, 0.24 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 85° C. overnight (prolonged heating in some caseswas required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh)eluting with 0-5% MeOH-DCM. The product was further purified by reversephase HPLC. Yield: 22 mg as TFA salt;

Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A:0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1.0 mL/min,Retention time: 10.094 min, HPLC purity: 98.06%;

¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.65 (m, 2H), 7.30 (s, 1H), 7.16 (m,2H), 7.06 (m, 2H), 6.90 (s, 1H), 4.80 (m, 2H), 4.38 (d, 1H), 3.90 (m,2H), 3.38 (m, 2H), 3.0 (m, 1H), 2.55 (m, 1H), 2.40 (s, 3H), 2.22 (m,2H), 1.90 (s, 3H).

Example 4 Preparation of(E)-7-(2-(4-fluorophenyl)prop-1-enyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole[Compound No. 4]

10-Methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (75 mg,0.33 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.03mmol), L-proline (7.5 mg, 0.066 mmol) and K₃PO₄ (139 mg, 0.65 mmol) wereadded and the reaction mixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (85 mg, 0.39 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 85° C. overnight (prolonged heating in some caseswas required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh)eluting with 0-5% MeOH-DCM. The product was further purified by reversephase HPLC. Yield: 18 mg;

Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A:0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1.0 mL/min,Retention time: 10.360 min, HPLC purity: 99.59%;

¹HNMR (CDCl₃, TFA salt) δ (ppm): 7.50 (m, 2H), 7.22 (s, 1H), 7.10 (m,4H), 6.80 (s, 1H), 4.82 (t, 1H), 3.55 (m, 1H), 3.40 (t, 2H), 3.0 (m,1H), 2.90 (t, 2H), 2.60 (m, 1H), 2.42 (s, 3H), 2.20 (m, 1H), 2.10 (m,1H), 2.0 (m, 1H), 1.90 (s, 3H).

Example 5 Preparation of(E)-5-(2-(4-fluorophenyl)prop-1-enyl)-2-methyl-5,6,6a,7,8,9,10,12-octahydroindolo[2,3-b]quinolizine[Compound No. 5]

2-Methyl-5,6,6a,7,8,9,10,12-octahydroindolo[2,3-b]quinolizine (100 mg,0.416 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7.9 mg,0.0416 mmol), L-proline (9.6 mg, 0.08 mmol) and K₃PO₄ (176 mg, 0.00832mmol) were added and the reaction mixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (107 mg, 0.005 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 85° C. overnight (prolonged heating in some caseswas required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh). Theproduct was further purified by reverse phase HPLC. Yield: 80 mg as TFAsalt;

Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A:0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1.0 mL/min,Retention time: 10.406 min, HPLC purity: 96.08%;

¹HNMR (CDCl₃, TFA salt) δ (ppm): 7.56 (m, 2H), 7.25 (s, 1H), 7.10 (m,4H), 6.82 (s, 1H), 5.90 (d, 1H), 4.0 (m, 2H), 3.30 (m, 2H), 2.90 (m,2H), 2.42 (s, 3H), 2.3-2.0 (m, 5H), 1.90 (s, 3H), 1.60 (m, 1H).

Example 6 Preparation of(E)-8-(2-(4-fluorophenyl)prop-1-enyl)-11-methyl-1,2,3,4,6,7,8,12c-octahydroindolo[3,2-a]quinolizine[Compound No. 6]

11-Methyl-1,2,3,4,6,7,7a,8,12b,12c-decahydroindolo[3,2-a]quinolizine(100 mg, 0.41 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7.9mg, 0.0416 mmol), L-proline (9.6 mg, 0.08 mmol) and K₃PO₄ (176 mg, 0.83mmol) were added and the reaction mixture was stirred for 10 min at RT.1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (107 mg, 53 mmol) was addeddropwise and the reaction mixture was purged with nitrogen. The reactionmixture was heated at 85° C. overnight (prolonged heating in some caseswas required). The DMF was evaporated under reduced pressure, theresidue was diluted with water and the solid was filtered. The solidmaterial was purified by silica gel chromatography (100-200 mesh)eluting with 0-5% MeOH-DCM. The product was further purified by reversephase HPLC. Yield: 13 mg as TFA salt;

Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase, Mobile Phase A:0.05% TFA, Mobile Phase B: Acetonitrile, Gradient, 10% to 90% B in 10min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1.0 mL/min,Retention time: 10.639 min, HPLC purity: 95.82%;

¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.65 (m, 2H), 7.45 (s, 1H), 7.18 (m,3H), 7.10 (d, 1H), 6.95 (s, 1H), 4.62 (m, 1H), 3.75 (m, 1H), 3.60 (m,2H), 3.40 (m, 3H), 3.10 (m, 2H), 2.42 (s, 3H), 2.10 (m, 2H), 1.90 (s,3H), 1.85 (m, 2H).

Example 7 Preparation of(E)-10-methyl-7-(2-(6-methylpyridin-3-yl)prop-1-enyl)-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole[Compound No. 32]

To a degassed solution of9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (50mg, 0.22 mmol), potassium phosphate (100 mg, 0.462 mmol), L-proline (5mg, 0.022 mmol) and copper iodide (5 mg, 0.044 mmol) in DMF (1 mL) wasadded 5-(2-bromo-1-methyl-vinyl)-2-methyl-pyridine (80 mg, 0.375 mmol).The reaction mixture was stirred at 120° C. for 20 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (3×10 mL). The organic layerwas washed with water (3×10 mL), followed by brine (15 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by reverse phase HPLC;

¹H NMR (CD₃OD, Di-HCl salt) δ (ppm): 9.0 (s, 1H), 8.8 (d, 1H), 8.0 (d,1H), 7.4 (d, 2H), 7.12 (m, 2H), 5.1 (m, 1H), 3.7-3.8 (m, 3H), 3.4-3.45(m, 2H), 3.15 (t, 2H), 2.83 (s, 3H), 2.8 (m, 1H), 2.42 (s, 3H), 2.22 (m,2H), 2.1 (s, 3H).

Example 8 Preparation of10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine[Compound No. 33]

To a solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solutionof 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 2 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by reverse phase HPLC to yield10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;

¹H NMR (CD₃OD, Tri-HCl salt) δ (ppm): 8.7 (s, 1H), 8.4 (d, 1H), 8.25 (s,2H), 7.8 (d, 1H), 5.1 (m, 1H), 4.8-4.6 (m, 2H), 3.9-3.7 (m, 3H), 3.4 (m,2H), 3.4-3.2 (m, 2H), 2.9-2.7 (m, 2H), 2.8 (s, 3H), 2.5 (s, 3H),2.3-2.15 (m, 3H).

Example 9 Preparation of7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine[Compound No. 34]

To a solution of2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solutionof 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (492 mg, 1.69mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 2 h at RT. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by silica gel flash chromatography (MeOH-DCM) to yield7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;

¹H NMR (CDCl₃, free base) δ (ppm): 8.3 (d, 1H), 8.18 (s, 1H), 7.7 (d,1H), 7.18 (d, 1H), 7.1-6.9 (m, 2H), 4.5-4.3 (m, 2H), 4.0 (m, 1H),3.3-3.2 (m, 1H), 3.19-3.0 (m, 2H), 2.9-2.7 (m, 3H), 2.59 (m, 1H), 2.5(s, 3H), 2.4 (m, 1H), 2.3-2.15 (m, 1H), 2.0-1.9 (m, 3H).

Example 10 Preparation of11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 35]

To a solution of7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(70 mg, 0.328 mmol) in DMF (1 mL) was added a suspension of NaH (40.0mg, 0.986 mmol) in DMF (1 mL). After stiffing for 5 min at RT, asolution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (287mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reactionmixture and stirring continued for another 2 h at RT. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (3×25 mL). The organic layerwas washed with water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by silica gel flash chromatography (MeOH-DCM) to yield11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;

¹H NMR (CDCl₃, free base) δ (ppm): 8.2 (d, 2H), 7.67 (d, 1H), 7.21 (d,1H), 7.0 (dd, 2H), 4.4-4.39 (m, 2H), 4.2 (d, 1H), 3.4-3.3 (m, 2H),3.10-2.95 (m, 2H), 2.6 (d, 1H), 2.5 (s, 3H), 2.41-2.39 (m, 3H), 2.1-1.8(m, 3H), 1.65-1.5 (m, 1H).

Example 11 Preparation of 3-methyl-1′-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 36]

To a solution of3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of NaH (42.0mg, 1.05 mmol) in DMF (1 mL). After stiffing for 5 min at rt, a solutionof 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (307 mg, 1.05mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 2 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by reverse phase HPLC to yield3-methyl-1′-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;

¹H NMR (CD₃OD, Tri-HCl salt) δ (ppm): 8.65 (s, 1H), 8.4 (d, 1H), 8.2 (s,1H), 8.19 (s, 1H), 7.8 (d, 1H), 4.8-4.6 (m, 4H), 4.4 (d, 1H), 4.0-3.8(m, 2H), 3.62 (dd, 1H), 3.5-3.3 (m, 2H), 3.1 (m, 1H), 2.79 (s, 3H),2.7-2.57 (m, 1H), 2.5 (s, 3H), 2.4-2.2 (m, 2H), 2.15-2.0 (m, 1H).

Example 12 Preparation of1-(piperidin-1-yl)-2-(8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)ethanone[Compound No. 37]

To a solution of7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(70 mg, 0.32 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg,0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of2-chloro-1-(piperidin-1-yl)ethanone (159 mg, 0.986 mmol) in DMF (1 mL)was added dropwise into the reaction mixture and stiffing continued foranother 3 h. The progress of reaction was monitored by TLC and NMR. Thereaction mixture was diluted with ice-water (20 mL) and extracted withEtOAc (3×25 mL). The organic layer was washed with water (3×20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude material, which was purified by silica gelflash chromatography (10% MeOH-DCM) to yield1-(piperidin-1-yl)-2-(8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)ethanone;

¹H NMR (CDCl₃, free base) δ (ppm): 8.18 (d, 1H), 7.7 (d, 1H), 7.0 (t,1H), 5.20 (d, 1H), 4.90 (d, 1H), 4.25 (d, 1H), 3.6-3.45 (m, 4H), 3.40(d, 1H), 3.25 (t, 2H), 3.05 (d, 1H), 2.65-2.55 (m, 2H), 2.40 (q, 1H),2.15 (m, 1H), 2.0 (m, 1H), 1.90 (m, 1H), 1.70-1.45 (m, 6H).

Example 13 Preparation of1-(piperidin-1-yl)-2-(2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)ethanone[Compound No. 38]

To a solution of2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0mg, 1.69 mmol) in DMF (1 mL). After stiffing for 5 min at RT, a solutionof 2-chloro-1-(piperidin-1-yl)ethanone (272 mg, 1.69 mmol) in DMF (1 mL)was added dropwise into the reaction mixture and stirring continued foranother 3 h. The progress of reaction was monitored by TLC and NMR. Thereaction mixture was diluted with ice-water (20 mL) and extracted withEtOAc (3×25 mL). The organic layer was washed with water (3×20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude material, which was purified by silica gelflash chromatography (10% MeOH-DCM) to yield1-(piperidin-1-yl)-2-(2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)ethanone;

¹H NMR (CDCl₃, free base) δ (ppm): 8.20 (d, 1H), 7.75 (d, 1H), 7.0 (m,1H), 5.05 (d, 1H), 4.25 (d, 1H), 4.20 (m, 1H), 3.6-3.5 (m, 3H),3.40-3.35 (m, 1H), 3.20-3.10 (m, 1H), 3.07-2.90 (m, 3H), 2.75-2.68 (m,1H), 2.5-2.40 (m, 1H), 2.05-1.85 (m, 3H), 1.70-1.60 (m, 2H), 1.60-1.45(m, 5H).

Example 14 Preparation of11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 39]

A solution of7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(70 mg, 0.328 mmol) and powdered KOH (128.5 mg, 2.296 mmol) in NMP (2mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine(113.5 mg, 0.656 mmol) was added into the reaction mixture and stiffingcontinued for 24 h at RT. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;

¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.40 (s, 1H), 8.2 (d, 1H), 7.95 (d,1H), 7.8 (d, 1H), 7.65 (d, 1H), 7.19 (m, 1H), 4.6 (t, 2H), 4.39 (d, 1H),3.9 (m, 1H), 3.8 (m, 1H), 3.5-3.3 (m, 2H), 3.3 (m, 3H), 3.1 (m, 1H), 2.6(m, 1H), 2.4-2.2 (m, 2H), 2.1-1.9 (m, 1H).

Example 15 Preparation of7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine[Compound No. 40]

A solution of2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(120 mg, 0.565 mmol) and powdered KOH (221.5 mg, 3.955 mmol) in NMP (2mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine(195.5 mg, 1.13 mmol) was added into the reaction mixture and stiffingcontinued for 24 h at RT. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;

¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.25 (d, 1H), 8.20 (s, 1H), 8.0 (d,1H), 7.8 (d, 1H), 7.65 (d, 1H), 7.19 (m, 1H), 5.10 (m, 1H), 4.65-4.5 (m,3H), 3.70-3.56 (m, 3H), 3.6-3.25 (m, 3H), 3.05-2.90 (m, 2H), 2.65 (m,1H), 2.25-2.2 (m, 2H).

Example 16 Preparation of2-(10-methyl-2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)-1-(piperidin-1-yl)ethanone[Compound No. 41]

To a solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of sodiumhydride (42 mg, 1.05 mmol) in DMF (1 mL). After stiffing for 5 min atRT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (114 mg, 0.704mmol) in DMF (1 mL) was added to the reaction mixture, and stiffingcontinued for 16 h. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield2-(10-methyl-2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)-1-(piperidin-1-yl)ethanone;

¹H NMR (CDCl₃, free base) δ (ppm): 8.0 (s, 1H), 7.55 (s, 1H), 5.0 (d,2H), 4.10 (m, 1H), 3.60-3.50 (m, 4H), 3.40-3.30 (m, 1H), 3.10-2.90 (m,2H), 2.80 (m, 1H), 2.65 (m, 1H), 2.45-2.35 (m, 5H), 2.0-1.8 (m, 3H),1.70-1.60 (m, 2H), 1.60-1.45 (m, 4H).

Example 17 Preparation of2-(3-methyl-8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)-1-(piperidin-1-yl)ethanone[Compound No. 42]

To a solution of3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(100 mg, 0.440 mmol) in DMF (1 mL) was added a suspension of sodiumhydride (52 mg, 1.32 mmol) in DMF (1 mL). After stirring for 5 min atRT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (142 mg, 0.881mmol) in DMF (1 mL) was added to the reaction mixture, and stirringcontinued for 2 h. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield2-(3-methyl-8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)-1-(piperidin-1-yl)ethanone;

¹H NMR (CDCl₃, free base) δ (ppm): 8.0 (s, 1H), 7.5 (s, 1H), 5.15 (d,1H), 4.85 (d, 1H), 4.20 (d, 1H), 3.6-3.45 (m, 4H), 3.40-3.25 (m, 2H),3.0 (d, 1H), 2.60 (m, 2H), 2.45-2.35 (m, 4H), 2.20-2.10 (m, 1H),2.0-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 3H), 1.50-1.45 (m,4H).

Example 18 Preparation of10-methyl-7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine[Compound No. 43]

A solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(80 mg, 0.352 mmol) and powdered KOH (138 mg, 2.46 mmol) in NMP (2 mL)was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (122mg, 0.704 mmol) was added into the reaction mixture and stiffingcontinued for 16 h. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield 10-methyl-7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;

¹H NMR (CDCl₃, free base) δ (ppm): 8.25 (s, 1H), 8.05 (s, 1H), 7.55 (s,1H), 7.45 (d, 1H), 7.40 (d, 1H), 4.50-4.30 (m, 2H), 3.95 (m, 1H),3.25-3.15 (m, 2H), 2.85-2.80 (m, 1H), 2.70 (t, 2H), 2.55-2.45 (m, 1H),2.40 (s, 3H), 2.30-2.20 (m, 2H), 1.90-1.75 (m, 4H).

Example 19 Preparation of3-methyl-1′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 44]

A solution of3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine(100 mg, 0.44 mmol) and powdered KOH (172.6 mg, 3.038 mmol) in NMP (2mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine(152 mg, 0.881 mmol) was added into the reaction mixture and stiffingcontinued for 16 h at RT. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel flash chromatography toyield3-methyl-1′-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;

¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.40 (s, 1H), 8.10 (s, 1H), 7.85 (s,1H), 7.80 (d, 1H), 7.60 (d, 1H), 4.55 (t, 2H), 4.35 (d, 1H), 3.90 (m,1H), 3.75 (m, 1H), 3.40-3.30 (m, 2H), 3.25 (t, 2H), 3.05 (m, 1H),2.60-2.50 (m, 1H), 2.45 (s, 3H), 2.40-2.20 (m, 2H), 2.0-1.90 (m, 2H).

Example 20 Preparation of7-(2-(pyridin-4-yl)-2-(hydroxy)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine[Compound No. 45]

To a stirred solution of2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (1 g, 4.6mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reaction masswas stirred at RT overnight. The progress of reaction was monitored byLCMS. The reaction mixture was quenched with ice cold water (300 mL) andextracted with EtOAc (3×100 mL). The combined organic layer was washedwith water (10×100 mL), followed by brine (2×100 mL), dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography followed by reverse phase HPLC to yieldthe title compound;

¹H NMR (CDCl₃, free base) δ (ppm): 8.56 (d, 1H), 8.50 (d, 1H), 8.30 (d,1H), 7.78 (d, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.10 (m, 1H), 5.20 (m,1H), 4.60 (m, 1H), 4.50 (dd, 1H), 4.28-4.18 (m, 1H), 3.10-3.0 (m, 4H),2.80 (m, 3H), 2.50 (m, 2H), 2.0 (m, 2H).

Example 21 Preparation of11-(2-(pyridin-4-yl)-2-(hydroxy)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 46]

To a stirred solution of2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (1 g,4.6 mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reactionmixture was stirred at RT overnight. The progress of reaction mass wasmonitored by LCMS. The reaction mixture was quenched with ice cold water(300 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layer was washed with water (10×100 mL) followed by brine (2×100mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography followed by reverse phase HPLC to yield the titlecompound.

Example 22 Preparation of3-chloro-11-(2-(pyridin-4-yl)-2-(hydroxy)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine[Compound No. 47]

To a stirred solution of6-chloro-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene(700 mg, 2.82 mmol) in DMF (10 mL) were added portionwise NaH (60%, 338mg 8.46 mmol) and 4-oxiranyl-pyridine (511 mg, 3.38 mmol). The reactionmass was stirred at RT for 16 h. The progress of reaction was monitoredby LCMS. The reaction mass was quenched with ice cold water (200 mL) andextracted with EtOAc (3×150 mL). The combined organic layer was washedwith water (10×100 mL) followed by brine (2×100 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography (0-15%DCM/MeOH) followed by reverse phase HPLC to yield the title compound;

¹H NMR (CDCl₃, free base) δ (ppm): 8.56 (d, 1H), 8.50 (d, 1H), 8.16 (s,1H), 7.68 (s, 1H), 7.36 (d, 1H), 7.20 (d, 1H), 5.16 (m, 1H), 4.78 (bs,1H), 4.42 (m, 1H), 4.25-4.15 (m, 2H), 3.30 (m, 2H), 2.56 (m, 2H), 2.40(m, 2H), 2.10 (m, 1H), 1.98 (m, 2H), 1.90 (m, 1H).

Example B1 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor

Histamine H₁

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₁ receptor expressed inChinese hamster ovary (CHO) cells [De Backer, M. et al., Biochem.Biophys. Res. Comm. (1993), 197(3):1601] in a modified Tris-HCl buffer(50 mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) wasused. Compounds of the invention were incubated with 1.2 nM[³H]Pyrilamine for 180 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM pyrilamine. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Pyrilaminespecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 2.

Histamine H₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₂ receptor expressed inChinese hamster ovary (CHO) K1 cells [Ruat, M., Proc. Natl. Acad. Sci.USA. (1990), 87(5):1658] in a 50 mM Phosphate buffer, pH 7.4 was used.Compounds of the invention were incubated with 0.1 nM[¹²⁵I]Aminopotentidine for 120 min at 25° C. Non-specific binding wasestimated in the presence of 3 μM Tiotidine. Receptor proteins werefiltered and washed, the filters were then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds were screened at 1μM or lower, using 1% DMSO as vehicle. Biochemical assay results arepresented as the percent inhibition of specific binding in Table 2.

Histamine H₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO-K1) cells [Yanai, K. et al., Jpn. J.Pharmacol. (1994), 65(2):107; Zhu, Y. et al., Mol. Pharmacol. (2001),59(3):434] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mMMgCl₂, 0.04% BSA) is used. Compounds of invention are incubated with 3nM [³H]R(−)-α-Methylhistamine for 90 min at 25° C. Non-specific bindingis estimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins are filtered and washed, the filters are then counted todetermine [³H] R(−)-α-Methylhistamine specifically bound. Compounds arescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention are tested in this biochemical assay and percent inhibition ofspecific binding is determined.

Example B2 Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor

Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex [Brown, C. et al., Br. J. Pharmacol. (1990), 99:803]in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mMEDTA) is used. Compounds of the invention are incubated with 2 nM[³H]Idazoxan for 30 min at 25° C. Non-specific binding is estimated inthe presence of 1 μM Idazoxan. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]Idazoxanspecifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

TABLE 2 Binding data (Percentage Inhibition) Compound No. H₁ H₂Histamine Binding (1 μM) 1 −2 15 2 9 17 3 88 97 4 41, 53 75 5 76 97 6 2867 Histamine Binding (0.1 μM) 32 1 33 73 34 22 35 50 36 96 37 6 38 5

Example B3 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor

Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands [Michel, A. D. et al., Br. J. Pharmacol. (1989),98:883] in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4,0.5 mM EDTA) was used. Compounds of the invention were incubated with0.25 nM [³H]Prozosin for 60 min at 25° C. Non-specific binding wasestimated in the presence of 10 μM phentolamine. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Prozosin specifically bound. Compounds of the invention werescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention were tested in this biochemical assay. Biochemical assayresults for representative compounds were presented as the percentinhibition of specific binding in Table 3.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver [Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun.(1992), 186:760; Michel, A. D. et al., Br. J. Pharmacol. (1989), 98:883]in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mMEDTA) was used. Compounds of the invention were incubated with 0.25 nM[³H]Prozosin for 60 min at 25° C. Non-specific binding was estimated inthe presence of 10 μM phentolamine. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Prozosinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay. Biochemical assay results for representativecompounds were presented as the percent inhibition of specific bindingin Table 3.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells [Kenny, B. A. et al., Br. J.Pharmacol. (1995), 115(6):981] in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prozosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prozosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention were tested in this biochemical assay.Biochemical assay results for representative compounds were presented asthe percent inhibition of specific binding in Table 3.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells [Uhlen, S. et al., J. Pharmacol. Exp. Ther. (1994),271:1558] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1nM [³H]MK-912 for 60 min at 25° C. MK912 was(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-one hydrochloride Non-specific binding was estimatedin the presence of 10 μM WB-4101(2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds ofthe invention were tested in this biochemical assay. Biochemical assayresults for representative compounds were presented as the percentinhibition of specific binding in Table 3.

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO-K1) cells [Uhlen, S. et al., Eur. J.Pharmacol. (1998), 343(1):93] in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used.Compounds of the invention were incubated with 2.5 nM [³H]Rauwolscinefor 60 min at 25° C. Non-specific binding was estimated in the presenceof 10 μM Prozosin. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Rauwolscine specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention were tested in this biochemicalassay. Biochemical assay results for representative compounds werepresented as the percent inhibition of specific binding in Table 3.

Adrenergic α_(2c)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2c) receptor expressed ininsect Sf9 cells [Uhlen, S. et al., J. Pharmacol. Exp. Ther. 1994),271:1558] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of the invention were incubatedwith 1 nM [³H]MK-912 for 60 min at 25° C. Non-specific binding wasestimated in the presence of 10 μM WB-4101. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]MK-912 specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay. Biochemical assay results for representativecompounds were presented as the percent inhibition of specific bindingin Table 3.

Example B4 Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor

Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D_(2L) receptor expressed inChinese hamster ovary (CHO) cells [Grandy, D. K. et al., Proc. Natl.Acad. Sci. USA. (1989), 86:9762; Hayes, G. et al., Mol. Endocrinol.(1992), 6:920] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,1.4 mM Ascorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds ofthe invention were incubated with 0.16 nM [³H]Spiperone for 120 min at25° C. Non-specific binding was estimated in the presence of 10 μMHaloperidol. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Spiperone specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 3.

TABLE 3 Percent Inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: AdrenergicDopamine (1 μM Compound (1 μM ligand conc.) ligand conc.) No. α_(1D)α_(2A) α_(2B) D_(2L) 1 15 22 55 9 2 23 20 51 13 3 11 4 90 5 28 6 94Dopamine (0.1 μM Compound Adrenergic (0.1 μM ligand conc.) ligand conc.)No. α_(1A) α_(1B) α_(1D) α_(2A) α_(2B) α_(2C) D_(2L)  4 59 32 55 93 8877 103 45 3 33 26 81 57 6 104 4 1 34 −9 2 15 −3 56 1 6 35 −2 −8 −1 7 332 −3 36 26 58 28 3 45 3 −3 37 −6 9 6 12 40 4 −5 38 −6 8 4 4 30 −6 24 39−4 40 50 41 14 42 3 43 98 44 17

Example B5 Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor

Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(1A) receptor expressed in Chinese hamster ovary (CHO-K1) cells[Martin, G. et al., Neuropharmacol. (1994), 33:261; May, J. A. et al.,J. Pharmacol. Exp. Ther. (2003), 306(1):301] in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mMMgSO₄) is used. Compounds of invention are incubated with 1.5 nM[³H]8-OH-DPAT for 60 min at 25° C. Non-specific binding is estimated inthe presence of 10 μM Metergoline. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H] 8-OH-DPATspecifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT_(1B) receptor fromWistar Rat cerebral cortex [Hoyer et al., Eur. J. Pharmaco. (1985),118:1; Pazos et al., Eur. J. Pharmacol. (1985), 106:531] in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline,30 μM Isoprenaline) is used. Compounds of invention are incubated with10 pM [¹²⁵I] Cyanopindolol for 90 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[¹²⁵I]Cyanopindolol specifically bound. Compounds are screened at 1 μMor lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO-K1) cells[Bonhaus, D. W. et al., Br. J. Pharmacol. (1995), 115:622; Saucier, C.et al., J. Neurochem. (1997), 68:1998] in a 50 mM Tris-HCl buffer, pH7.4, was used. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Ketanserinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2B) receptor expressed in Chinese hamster ovary (CHO-K1) cells[Bonhaus, D. W. et al., Br. J. Pharmacol. (1995), 115:622] in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid)is used. Compounds of invention are incubated with 1.2 nM [³H]Lysergicacid diethylamide (LSD) for 60 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2C) receptor expressed in Chinese hamster ovary (CHO-K1) cells[Wolf, W. et al., J. Neurochem. (1997), 69:1449] in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10 μM Pargyline) wasused. Compounds of the invention were incubated with 1 nM[³H]Mesulergine for 60 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Mesulerginespecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells [Miller, Ket al., Synapase. (1992), 11:58; Boess, F. G. et al., Neuropharmacology(1997), 36:637] in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1mM EDTA, 5 mM MgCl₂) is used. Compounds of invention are incubated with0.69 nM [³H]GR-65630 for 60 min at 25° C. Non-specific binding isestimated in the presence of 10 μM MDL-72222. Receptor proteins arefiltered and washed, the filters are then counted to determine[³H]GR-65630 specifically bound. Compounds are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum [Grossman, C. J. et al., Br.J. Pharmacol. (1993), 109:618] in a 50 mM Tris-HCl, pH 7.4, is used.Compounds of invention are incubated with 0.7 nM [³H]GR-113808 for 30min at 25° C. Non-specific binding is estimated in the presence of 30 μMSerotonin (5-HT). Receptor proteins are filtered and washed, the filtersare then counted to determine [³H]GR-113808 specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(5A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(5A) receptor expressed in Chinese hamster ovary (CHO-K1) cells[Rees, S. et al., FEBS Lett. (1994), 355:242] in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used.Compounds of the invention were incubated with 1.7 nM [³H]Lysergic aciddiethylamide (LSD) for 60 min at 37° C. Non-specific binding wasestimated in the presence of 100 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[³H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₆receptor expressed in human HeLa cells [Monsma, F. J. Jr. et al., Mol.Pharmacol. (1993), 43:320] in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used.Compounds of the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 min at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT_(S)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇receptor expressed in Chinese hamster ovary (CHO) cells [Roth, B. L. etal., J. Pharmacol. Exp. Ther. (1994), 268:1403; Shen, Y. et al., J.Biol. Chem. (1993), 268:18200] in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds ofinvention were incubated with 5.5 nM [³H] Lysergic acid diethylamide(LSD) for 2 h at 25° C. Non-specific binding was estimated in thepresence of 10 μM Serotonin (5-HT). Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]LSD specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

TABLE 4 Percent Inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: CompoundSerotonin (1 μM ligand concentration) No. 5-HT_(2A) 5-HT_(2C) 5-HT₆5-HT₇ 1 11 44 19 2 41 53 19 3 90 99 101 94 4 99 99 103 101 5 98 92 96 976 99 94 105 92 Compound Serotonin (0.1 μM ligand concentration) No.5-HT_(2A) 5-HT_(2C) 5-HT_(5A) 5-HT₆ 5-HT₇ 4 87 88 100 32 50 26 24 25 6133 29 13 0 20 44 34 15 7 6 5 18 35 31 15 10 −3 6 36 35 19 25 34 23 37 339 8 −9 3 38 19 16 8 −8 23 39 24 −5 2 40 6 1 10 41 −2 8 −5 42 1 2 −1 43 75 22 44 65 9 24

Example B6 Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A)Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells [Jerman, J.et al., Eur. J. Pharmacol. (2001), 414:23-30] is used. Cells aresuspended in DMEM buffer, and distributed in microplates. A cytoplasmiccalcium fluorescent indicator which varies proportionally to the freecytosolic Ca²⁺ ion concentration is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4), added into each well andequilibrated with the cells for 30 min at 37° C. followed by 30 min at22° C.

To measure agonist effects, compounds of the invention, referenceagonist or HBSS buffer (basal control) is added to the cells and changesin fluorescence intensity are measured using a microplate reader. Forstimulated control measurements, 5-HT at 100 nM is added in separateassay wells.

The results are expressed as a percent of the control response to 100 nM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 3 nM 5-HT or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as a percentinhibition of the control response to 3 nM 5-HT. The standard referenceantagonist is ketanserin, which is tested in each experiment at severalconcentrations to generate a concentration-response curve from which itsIC₅₀ value is calculated. Compounds are screened at 3 μM or lower, usingDMSO as vehicle.

Example B7 Determination of Serotonin (5-Hydroxytryptamine) 5-HT₆Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells [Kohen, R. et al., J. Neurochem. (1996), 66:47]and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min at RT, the fluorescence transfer is measured at lex=337 nmand lem=620 and 665 nm using a microplate reader. The cAMP concentrationis determined by dividing the signal measured at 665 nm by that measuredat 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D₂-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min at RT, the fluorescence transfer is measured as mentionedabove. The results are expressed as a percent inhibition of the controlresponse to 100 nM 5-HT. The standard reference antagonist ismethiothepin

Example B8 Determination of Dopamine D₂₁ Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2L)receptor stably expressed in Chinese hamster ovary (CHO) cells[Senogles, S. et al., J. Biol. Chem. (1990), 265(8):4507] is used.Compounds of invention are pre-incubated with the membranes (0.1 mg/mL)and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mMNaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 min and ScintillationProximity Assay (SPA) beads are added for another 60 min at 30° C. Thereaction is initiated by 0.3 nM [³⁵S]GTPγS for an additional 15 minuteincubation period. Increase of [³⁵S]GTPγS binding by 50% or more (350%)relative to the 1 mM dopamine response by compounds of the inventionindicates possible dopamine D_(2L) receptor agonist activity. Inhibitionof a 10 μM dopamine-induced increase of [³⁵S]GTPγS binding response by50% or more (350%) by compounds of the invention indicates receptorantagonist activity. Compounds are screened at 3 μM or lower, using 0.4%DMSO as vehicle. Assay results are presented as the percent response ofspecific binding.

Example B9 Determination of Dopamine D_(2S) Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2S)receptor stably expressed in Chinese hamster ovary (CHO) cells[Gilliland, S. et al., Naunyn-Schmiedeberg's Archives of Pharmacology(2000), 361:498] is used. Compounds of invention are pre-incubated withthe membranes (0.05 mg/mL) and 3 μM GDP in modified HEPES buffer (20 mMHEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 minand Scintillation Proximity Assay (SPA) beads are then added for another60 min at 30° C. The reaction is initiated by 0.3 nM [³⁵S]GTPγS for anadditional 30 minute incubation period. Increase of [³⁵S]GTPγS bindingby 50% or more (350%) relative to the 100 μM dopamine response bycompounds of the invention indicates possible dopamine D_(2S) receptoragonist activity. Inhibition of a 3 μM dopamine-induced increase of[³⁵S]GTPγS binding response by 50% or more (350%) by compounds of theinvention indicates receptor antagonist activity. Compounds are screenedat 3 μM or lower, using 0.4% DMSO as vehicle. Assay results arepresented as the percent response of specific binding.

Example B10 Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H₁ Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H₁ receptorexpressed in human embryonic kidney (HEK-293) cells [Miller, T. et al.,J. Biomol. Screen. (1999), 4:249-258] is used. Cells are suspended inDMEM buffer, and then distributed in microplates. A cytoplasmic calciumfluorescent indicator—which varies proportionally to the free cytosolicCa²⁺ ion concentration—is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4) and is then added into each welland equilibrated with the cells for 30 min at 37° C. and then foranother 30 min at 22° C. To measure agonist effects, compounds of theinvention, reference agonist or HBSS buffer (basal control) are added tothe cells and changes in fluorescence intensity are measured using amicroplate reader. For stimulated control measurements, histamine at 10μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example B11 Increase of Neurite Outgrowth

Neurite Outgrowth in Cortical Neurons

Compounds are tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods are used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation is prepared inLeibovitz's medium (L15; Gibco). The cortex is dissected out, and themeninges are removed. Trypsin (Gibco) is used to dissociate cortical Cwith DNAse I. The cells are triturated for 30 min with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 min at RT. Thecells are suspended in Neurobasal medium supplemented with 2% B27(Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at30,000 cells per well of poly-L-lysine coated plates at 37° C. in 5%CO₂-95% air atmosphere. After adhesion, a vehicle control or compoundsof the invention are added at different concentrations to the medium.BDNF (50 ng/mL) is used as a positive control for neurite growth. Aftertreatment, cultures are washed in phosphate-buffered saline (“PBS”;Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3days growth. Several pictures (˜80) of cells with neurites are taken percondition with a camera. The length measurements are made by analysis ofthe pictures using software from Image-Pro Plus (France). The resultsare expressed as mean (s.e.m.). Statistical analysis of the data isperformed using one way analysis of variance (ANOVA).

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures are prepared from E18 Wistar rat embryos. Thecortices are dissected out and the tissue was cut to small pieces. Thecells are separated by 15-min incubation with DNase and papain. Thecells are collected by centrifugation (1500 rpm, 5 min). The tissue istriturated with a pipette and the cells are plated using the micro-isletprotocol (20 000 cells in 25 μL medium) on poly-L-lysine coated 48wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin,10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells attach to thewell, 250 μL medium is added to the wells. Four hours after plating themedium is changed to fresh medium (MEM with supplements and 5% HS-HI)containing test compound at 0.5, 5 and 50 nM concentrations. As positivecontrols BDNF (50, 100 and/or 150 ng/mL), and/or NGF (50 ng/mL and/or100 ng/mL) are used. After 2 days in vitro, the cell's conditioned mediaare collected from plates before fixing the cells. The media samples arecentrifuged 13 000 rpm 3 min to get rid of cell debris. The samples arestored at −20° C. for later analysis. Cells are formaldehyde-fixed andprocessed for immunocytochemistry. BDNF levels in the conditioned mediaare determined with a BDNF ELISA using the manufacturers (Promega, BDNFEmax® ImmunoAssay System, catalog number: G7610) instructions.

The cultures are fixed with 4% formaldehyde in 0.01M PBS for 30 min andwashed once with PBS. The fixed cells are first permeabilized andnon-specific binding is blocked by a 30-min incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) is used as a primary antibody. The cells are incubated with theprimary antibody for 48 h at +4° C., washed with PBS and incubated withsecondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568(1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositivecells are visualized by a fluorescence microscope equipped withappropriate filter set, and documented by a high resolution imagecapturing. The number of cells per field (4 field per well) are counted,and the neurite outgrowth is quantified using Image Pro Plus software.

The number of wells per compound concentration used is 6 (n=6). All dataare presented as mean±standard deviation (SD) or standard error of mean(SEM), and differences are considered to be statistically significant atthe p<0.05 level. Statistical analysis is performed using StatsDirectstatistical software. Differences between group means are analyzed byusing 1-way-ANOVA followed by Dunnet's test (comparison to the vehicletreated group).

Example B12 Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat is used as a model of episodic/short-term memory[Ennaceur, A. et al., Behav. Brain Res. (1988), 31:47-59]. The paradigmis based on spontaneous exploratory activity of rodents and does notinvolve rule learning or reinforcement. The novel object recognitionparadigm is sensitive to the effects of ageing and cholinergicdysfunction [Scali, C. et al., Neurosci. Letts. (1994), 170:117-120;Bartolini, L. et al., Biochem. Behav. (1996), 53:277-283].

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams are obtained, e.g., from Centre d'Elevage (RueJanvier, B. P. 55, Le Genest-Saint-Isle 53940, France). The animals arehoused in groups of 2 to 4 in polypropylene cages (with a floor area of1032 cm²) under standard conditions: at RT (22±2° C.), under a 12 hlight/12 h dark cycle, with food and water provided ad libitum. Animalsare permitted to acclimate to environmental conditions for at least 5days before the experiment begins, and are numbered on their tails withindelible marker.

The experimental arena is a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena arecleaned with water between each trial to eliminate any odor trails leftby rats. The arena is placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals are allowed to freely explore the experimental arena for 3 minin the presence of two objects (habituation). Animals to be tested areplaced in the experimental room at least 30 min before testing.

Novel object recognition test is comprised of two trials separated by aninterval of 120 min or 24 h. When agents that disrupt memory such as thecholinergic antagonist scopolamine are used an inter-trial interval of120 min is preferred. Alternatively a 24 h inter-trial interval is usedwhen studying effect of natural forgetting on novel object recognitiontask. During the first, or acquisition, trial (T₁), rats are placed inthe arena, where two identical objects have been previously placed. Thetime required for each animal to complete 15 sec of object explorationis determined, with a cut-off time of 4 min. Exploration is consideredto be directing the nose at a distance less than 2 centimeters (“cm”)from the object and/or touching the object. During the second, ortesting, trial (T₂), one of the objects presented in the first trial isreplaced with an unknown or novel object, while the second, familiarobject is left in place. Rats are placed back in the arena for 3 min,and exploration of both objects is determined. Locomotor activity ofrats (number of times rats cross grid lines visible under the clearplexiglass floor) is scored for during T₁ and T₂. At the conclusion ofthe experiments, the rats are sacrificed by an overdose of pentobarbitalgiven intraperitoneally.

The following parameters are measured as part of the novel objectrecognition task: (1) time required to achieve 15 sec of objectexploration during T₁; (2) locomotor activity during T₁ (number ofcrossed lines); (3) time spent in active exploration of the familiarobject during T₂ (T_(Familiar)); (4) time spent in active exploration ofthe novel object during T₂ (T_(Novel)); and (5) locomotor activityduring T₂ (number of crossed lines). The difference between time spentin active exploration of the novel object during T₂ and time spent inactive exploration of the familiar object during T₂ (ΔT_(Novel)−T_(Familiar)) is evaluated. The % of animals in each groupwith T_(Novel)−T_(Familiar) greater than or equal to 5 sec is alsoderived; described as % of good learners.

Animals not meeting a minimal level of object exploration are excludedfrom the study as having naturally low levels of spontaneousexploration. Thus, only rats exploring the objects for at least five sec(T_(Novel)+T_(Familiar)>5 sec) are included in the study.

Animals are randomly assigned to groups of 14. Compounds of theinvention and controls are administered to animals the groups asfollows: Solutions of compounds are prepared freshly each day at aconcentration of 0.25 mg/mL using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine are administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil or its vehicle and scopolamine are administeredintraperitoneally forty min before the acquisition trial (T₁). Compoundsor their vehicle are administered by gavage 25 min before theacquisition trial (T₁), i.e., 5 min after administration of scopolamine.The volume of administration is 5 mL/kg body weight for compoundsadministered intraperitoneally, and 10 mL/kg for compounds administeredorally. Recognition scores and percent of good learners for compoundsare determined.

Example B13 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in PCP Treated Animals

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidine (PCP), which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans [Jentsch et al., Science (1997), 277:953-955;Piercey et al., Life Sci. (1988), 43(4):375-385]. Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male mice (various strains, e.g., C57B1/6J) from appropriate vendor (forexample, Jackson Laboratories (Bar Harbor, Me.) are used. Mice arereceived at 6-weeks of age. Upon receipt, mice are assigned uniqueidentification numbers (tail marked) and are group housed with 4mice/cage in OPTI mouse ventilated cages. All animals remain housed ingroups of four during the remainder of the study. All mice areacclimated to the colony room for at least 2 weeks prior to testing andare subsequently tested at an average age of 8 weeks. During the periodof acclimation, mice are examined on a regular basis, handled, andweighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The RT is maintained between 20and 23° C. with a relative humidity maintained between 30% and 70%. Foodand water are provided ad libitum for the duration of the study. In eachtest, animals are randomly assigned across treatment groups.

The open filed (OF) test assesses locomotor behavior, i.e. to measuremouse locomotor activity at baseline and in response to pharmacologicalagents. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone such that the infrared photobeams allowmeasurement of activity in the center and periphery of the field.Distance traveled is measured from horizontal beam breaks as the mousemoved whereas rearing activity is measured from vertical beam breaks.

Mice (10 to 12 animals per treatment group) are brought to the activityexperimental room for at least 1 h acclimation to the experimental roomconditions prior to testing. Eight animals are tested in each run. Miceare administered vehicle (e.g. 10% DMSO or 5% PEG200 and 1% Tween 80),compound of the invention, clozapine (positive control, 1 mg/kg ip) andplaced in the OF chambers for 30 min following which they are injectedwith either water or PCP and placed back in the OF chambers for a 60-minsession. At the end of each OF test session the OF chambers arethoroughly cleaned.

PCP Hyperactivity Mouse Model of Schizophrenia

The test compound at the desired dose is dissolved in appropriatevehicle, e.g., 5% PEG200, 1% Tween80 and administered orally 30 minprior to PCP injection. Clozapine (1 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min prior to PCP injection. PCP (5 mg/kg) isdissolved in sterile injectable saline solution and administered i.p.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity is measured during the 60 min following PCPinjection. Statistical outliers that fell above or below 2 standarddeviations from the mean are removed from the final analyses. An effectis considered significant if p<0.05. Total distances traveled and totalrearing following PCP administration are compared between groups treatedwith compounds and groups treated with vehicle and positive controlclozapine.

Example B14 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in Amphetamine Treated Animals

Male mice (various strains e.g., C57B1/6J) from appropriate supplier(for example Jackson Laboratories, Bar Harbor, Me.) are used. Micetypically are received at 6-weeks of age. Mice are acclimated to thecolony room for at least 2 weeks prior to testing. During the period ofacclimation, mice are examined on a regular basis, handled, and weighedto assure adequate health and suitability and maintained on a 12/12light/dark cycle. The room temperature is maintained between 20 and 23°C. with a relative humidity maintained between 30% and 70%. Food andwater are provided ad libitum for the duration of the study. In eachtest, animals are randomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglass square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 h acclimation prior to start of treatment. Animals areadministered with vehicle, haloperidol (positive control, 0.1 mg/kg ip)or test compound and placed in the OF. The time of administration ofclient compound to each animal is recorded. Baseline activity isrecorded for 30 min following which mice receive amphetamine (4 mg/kg)or water and are placed back in the OF chambers for a 60-min session. Atthe end of each open field test session the OF chambers are thoroughlycleaned. Typically ten to twelve mice are tested in each group. Testcompound doses typically range from 0.01 mg/kg to 60 mg/kg.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to amphetamineinjection. Amphetamine-induced activity is measured during the 60 minfollowing amphetamine injection. Statistical outliers that fall above orbelow 2 standard deviations from the mean are removed from the finalanalyses. An effect is considered significant if p<0.05. Total distancetraveled and total rearing following amphetamine administration arecompared between groups treated with compound and groups treated withvehicle and positive control haloperidol.

Example B15 Use of the In Vivo Conditioned Avoidance Response (Car)Model to Determine the Ability of Compounds to Treat, Prevent and/orDelay the Onset and/or the Development of Schizophrenia

All currently approved antipsychotic agents (typical and atypical) areknown to have the ability to selectively suppress conditioned avoidanceresponse (CAR) behavior in the rat. This evidence makes CAR one of theprimary tests to assess antipsychotic activity of novel compounds.

Rats (various strains, 2 months of age) are trained and tested in acomputer-assisted, two-way active avoidance apparatus (shuttle box).This box consists of two compartments of equal size divided by astainless steel partition containing an opening of 7×7 cm. Eachcompartment is equipped with an electrified grid floor made of stainlesssteel rods spaced 1 cm apart. Rats trained to avoid the foot shock areplaced each day in the shuttle box for a 4 min habituation periodfollowed by 30 trials spaced by inter-trial interval varying at randombetween 20 and 30 sec. Each trial consists of a 10-sec stimulus light(conditioned stimulus, CS) followed by a 10-sec foot shock(unconditioned stimulus, US) in presence of the light presented in thecompartment where the rat is located. If the animal leaves thecompartment prior to the delivery of the foot shock, the response isconsidered an avoidance response. If the rat does not change compartmentduring the 10-sec light period and during the 10-sec shock+light period,an escape failure is recorded. This test requires animals to be trained5 days/week. On each training day, rats are submitted to one trainingsession of 30-trials. Treatment with test compound is initiated onlywhen rats reach an avoidance performance of at least 80% on at least twoconsecutive training sessions. The test compound is administered orallyat various doses and various pre-treatment times (depending uponspecific pharmacokinetic properties).

Compounds with antipsychotic profile inhibit conditioned avoidanceresponses with or without increases in escape failures. Statisticalanalysis is performed using a Friedman two-way ANOVA by ranks followedby the Wilcoxon matched-pairs signed-ranks test to test each dose of thetest compound administered versus vehicle control treated rats. Theability of compounds of the invention to bind receptors detailedhereinabove is evaluated in multiple concentrations.

Example B16 Use of the 5-Choice Serial Reaction Task to Determine theAbility of Compounds to Enhance Attention/Vigilance and ReduceImpulsivity

Attention and impulsivity are characteristic of several disease states.The continuous performance test (CPT), used in humans, is capable ofdetecting attention deficits in a number of disorders, includingattention deficit hyperactivity disorder [Riccio et al., J.Neuropsychiatry Clin. Neurosci (2001), 13(3):326-335], schizophrenia[Lee et al., Schizophr. Res. (2006), 81(2-3):191-197], and mildcognitive impairment [Levinoff et al., Neuropsychology (2006),20(1):123-132]. The pre-clinical analogue of the CPT is the 5-choiceserial reaction time task [“5-CSRTT”; Robbins, T., Psychopharmacology(2002), 3-4:362-380]. In this operant-based test, rats are required tobe attentive and withhold responding while they monitor 5 apertures forthe appearance of a brief stimulus light in one of the apertures. Thebrief illumination of the stimulus light in the 5-CSRTT is analogous tothe appearance of the “correct” letters in the CPT in humans. Uponobserving the stimulus light, the rat must nose-poke in thecorresponding aperture to receive a food reward. The 5-CSRTT allows themeasurement of similar behavioral responses as the CPT, includingaccuracy, speed of responding, impulsive and compulsive responding. Inthe present studies, drug tests are performed under altered testparameters which results in increased premature responding. Thispremature responding is hypothesized to indicate impulsivity, i.e., afailure to withhold an inappropriate response, and has been shown to besensitive to atomoxetine [Navarra et al., Prog. Neuropsychopharmacol.Biol. Psychiatry (2008), 32(1):34-41].

A minimum of 12 male Long-Evans rats (275-300 g) are obtained fromHarlan Laboratories, Indianapolis, Ind. At the time of testing, rats areapproximately 16-18 months old. Upon arrival, the rats are assignedunique identification numbers (tail marked). Rats are single-housed inOptiRAT cages and acclimated for 7 days prior to commencing afood-restriction regimen: rats are held at 85% of age-matchedfree-feeding control body-weights, receiving approximately 10-20 g ofrat chow daily. Water is provided ad libitum, except during testing.Animals are maintained in a 12/12 h light/dark cycle (lights on at 0700EST) with RT maintained at 22±2° C. and the relative humidity maintainedat approximately 50%. All animals are examined, handled and weighedprior to initiation of the study to assure adequate health andsuitability and to minimize non-specific stress associated with testing.The 5-CSRTT sessions are performed during the animal's light cyclephase. All experiments and procedures are approved by the InstitutionalAnimal Care and Use Committee of PsychoGenics, Inc.

Apparatus: The apparatus consists of aluminum and Plexiglas chamberswith grid floors (width 31.5 cm, depth 25.0 cm, height 33.0 cm), housedin sound-attenuating cabinets. Each cabinet is fitted with a low-levelnoise extractor fan which also helps to mask external noise. The leftwall of each chamber is concavely curved with 5 apertures evenly spaced,located approximately 2.5 cm from the floor. Each aperture contains astandard 3W LED to serve as stimulus lights. The opposite wall containsa food magazine, located approximately 3.0 cm from the floor. Eachchamber is illuminated with a 3W house-light located in the center ofthe ceiling panel. After each test session the apparatus is cleaned with70% EtOH.

Experimental procedure: Training: Animals are trained to monitor thefive apertures for stimulus light illumination. Each session isinitiated by the illumination of the house light, and the delivery of afood reward into the magazine. The first trial begins when the rat opensthe magazine to obtain the food pellet. After the inter-trial interval(ITI) one of the stimulus lights is illuminated for 500 msec. The ratmust nose-poke in the illuminated aperture either during or within 5 secof stimulus light illumination. Such a response is defined as a correctresponse, and is rewarded with delivery of a food pellet. Collection ofthe pellet initiates the next trial. A nose-poke response in anon-illuminated aperture (incorrect response) or a nose-poke after the 5sec limited hold (missed trial) results in termination of the trial withextinction of the house-light and imposition of a time-out period.Testing: After acquisition of the 5-CSRTT with a high level of accuracy(at least 75% correct, at least 50 trials completed per session), drugtesting begins. Animals are treated with test compound (various doses,appropriate vehicle), vehicle and positive control (atomoxetine 1 mg/kgip). During drug test sessions, the ITI is varied between 10, 7, 5 or 4sec in duration, presented in groups of 4 trials (each of which contains1 trial at each ITI duration in a randomized order). The session endswhen 60 min have elapsed. All rats receive all drug treatments,according to a randomized-order within-subjects design. Drug tests areperformed on Wednesdays and Fridays of each week, only when rats haveperformed at least 75% correct trials for a minimum of 50 trials in theprevious test session.

Measures obtained during the test sessions are: (1) percent correct,defined as the number of correct trials X 100, divided by the totalnumber of correct and incorrect trials, (2) missed trials, defined asresponding beyond the 5 sec limited hold or failing to respond, (3)correct latency, defined as the time taken to make a correct responseafter the illumination of the stimulus, (4) magazine latency, defined asthe time taken to enter the magazine to collect the food pellet aftermaking a correct response, (5) premature responding, defined as thetotal number of nose-poke responses made during the ITI, and (6)preservative responding, defined as the total number of additionalresponses emitted after the initial nose-poke.

Statistical Analysis

Data are expressed as percent correct; the numbers of missed trials,preliminary and preservative responses; and latencies (in sec) to makecorrect responses and to collect food pellets after a correct response.Data are analyzed by analyses of variance (ANOVA). In all cases, valuesof p<0.05 are considered to be significant. Post-hoc comparisons aremade using Fisher LSD post-hoc tests where appropriate.

Example B17 An Animal Model of the Negative Symptoms of Schizophrenia:Subchronic PCP-Induced Social Interaction Deficits

Phencyclidine (PCP) administered to humans as well to experimentalanimals induces full-spectrum of schizophrenia symptoms, includingnegative symptoms and cognitive deficits. A major symptom ofschizophrenia is considered to be social isolation/withdrawal as part ofthe cluster of negative symptoms. Subchronic treatment with PCP in ratsleads to the development of clear signs of social withdrawal as measuredby deficits in the interaction time with a cage intruder rat. MaleSprague Dawley rats (about 150 g, obtained from different vendors, forexample Harlan, Ind.) are used in this study. Upon receipt, rats aregroup housed in OPTI rat ventilated cages. Rats are housed in groups of2-3 per cage for the remainder of the study. During the period ofacclimation, rats are examined on a regular basis, handled, and weighedto assure adequate health and suitability. Rats are maintained on a12/12 light/dark cycle with the light on at 7:00 a.m. The roomtemperature is maintained between 20-23° C. with a relative humiditymaintained between 30-70%. Food and water are provided ad libitum forthe duration of the study. Animals are randomly assigned acrosstreatment groups and balanced by age.

For five days prior to test, rats are injected twice daily with eitherPCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 minpretreatment with vehicle, clozapine (2.5 mg/kg ip dissolved in 5% PEG:5% Tween 80) as positive control and test compound at desired dosedissolved in appropriate vehicle, a pair of rats, unfamiliar to eachother, receiving the same treatment are placed in a white plexiglas openfield arena (24″×17″×8″) and allowed to interact with each other for 6min. Social interactions (‘SI’) include: sniffing the other rat;grooming the other rat; climbing over or under or around the other rat;following the other rat; or exploring the ano-genital area of the otherrat. Passive contact and aggressive contact are not considered a measureof social interaction. The time the rats spent interacting with eachother during the 6 min test is recorded by a trained observer. Thesocial interaction chambers are thoroughly cleaned between the differentrats. Data are analyzed by analysis of variance (ANOVA) followed bypost-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effectis considered significant if p<0.05.

Example B18 An Animal Model of Extrapyramidal Syndrome (EPS):Measurement of Catalepsy in the Mouse Bar Test

Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) inanimals and in humans. An animal model considered to be predictive ofEPS is the mouse bar test, which measures cataleptic responses topharmacological agents. Male mice (various strains) from appropriatevendor (for example, Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice per cage in OPTI mouse ventilated cages. All animals remain housedin groups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20-23° C. with a relative humidity maintained between30-70%. Food and water are provided ad libitum for the duration of thestudy. In each test, animals are randomly assigned across treatmentgroups.

In the mouse bar test, the front paws of a mouse are placed on ahorizontal bar raised 2″ above a Plexiglas platform and time is recordedfor up to 30 sec per trial. The test ends when the animal's front pawsreturn to the platform or after 30 sec. The test is repeated 3 times andthe average of 3 trials is recorded as index of catalepsy. In thesestudies the typical antipsychotic agent haloperidol (2 mg/kg ipdissolved in 10% DMSO) is used as positive control and induces rigidityand catalepsy as measured by time spent holding on the bar. 30 min priorto the trial, test compound at desired dose and dissolved in appropriatevehicle is administered PO, vehicle and positive control haloperidol (2mg/kg ip) are administered to separate groups of mice. Catalepsyresponses are measure 30 min, 1 h and 3 h following treatments. Atrained observer is measuring time spent holding onto the bar during the30 sec trial. Data are analyzed by analysis of variance (ANOVA) followedby post-hoc analysis (e.g., Fischer, Dunnett) when appropriate. Aneffect is considered significant if p<0.05.

Example B19 An Animal Model to Test the Anxiolytic Effects of CompoundsUsing the Elevated Plus Maze (EPM) Test

This study may be used to test the anxiolytic properties of compoundsdetailed herein using the elevated plus maze (EPM) test in C57B1/6Jmice.

Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Me.) are usedfor the open field study. Mice are received at 6-weeks of age. Uponreceipt, mice are assigned unique identification numbers (tail marked)and are group housed with 4 mice/cage in OPTI mouse ventilated cages.All animals remain housed in groups of four during the remainder of thestudy. All mice are acclimated to the colony room for approximately 2week prior to testing and are subsequently tested at an average age of 8weeks of age. During the period of acclimation, mice and rats areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability. Animals are maintained on a 12 h/12 h light/darkcycle. The room temperature is maintained between 20 and 23° C. with arelative humidity maintained between 30% and 70%. Chow and water areprovided ad libitum for the duration of the study. In each test, animalsare randomly assigned across treatment groups. All animals areeuthanized after the completion of the study.

Compounds may be dissolved in 5% PEG200/H₂O and administered orally at adose volume of 10 mL/kg 30 min prior to test; 2) Diazepam (2.5 mg/kg) isdissolved in 45% hydroxypropyl-β-cyclodextrin and administered orally ata dose volume of 10 mL/kg 30 min prior to test.

The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder)consists of two closed arms (14.5 h×5 w×35 cm length) and two open arms(6 w×35 1 cm) forming a cross, with a square center platform (6×6 cm).All visible surfaces are made of black acrylic. Each arm of the maze isplaced on a support column 56 cm above the floor. Antistatic black vinylcurtains (7′ tall) surround the EPM to make a 5′×5″ enclosure. Animalsare brought to acclimate to the experimental room at least 1 h beforethe test. Mice are placed in the center of the elevated plus maze facingthe closed arm for a 5-min run. All animals are tested once. The timespent, distance traveled and entries in each arm are automaticallyrecorded by a computer. The EPM is thoroughly cleaned after each mouse.

Data are analyzed using analysis of variance (ANOVA) followed byFisher's LSD post hoc analysis when appropriate. An effect is consideredsignificant if p<0.05.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

The invention claimed is:
 1. A compound of the formula (Ii):

wherein: R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(10a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R^(2a)and R^(2b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety; each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy,substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl,heterocyclyl, acylamino, acyloxy or R^(3a) and R^(3b) are taken togetherwith the carbon to which they are attached to form a carbonyl moiety ora cycloalkyl moiety, or R^(3a) and R^(10a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;X⁷, is N or CR^(4a); each R⁴ and R^(4a) is independently H, hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8c),R^(8d),R^(8e) and R^(8f) is independently H, hydroxyl, alkoxy,halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstitutedC₂-C₈alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl or istaken together with a geminal R^(8(c-f)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(c-f)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety; eachR^(10a) and R^(10b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy or R^(10a) and R^(10b)are taken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(10a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(10a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety; and Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy or acylamino; provided that the compound conforms toone of provisions (i)-(iii): (i) R¹ and R^(2a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety; (ii) R¹ and R^(10a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; and (iii)R^(3a) and R^(10a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein X⁷, isCR^(4a) where R^(4a) is H, or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1, wherein R^(8c) and R^(8d) are bothH, or a pharmaceutically acceptable salt thereof.
 4. A compound, or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:


5. The compound of claim 1, wherein R¹ and R^(2a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety; or a pharmaceutically acceptablesalt thereof.
 6. The compound of claim 5, wherein R^(8c) and R^(8d) areeach H and at least one of R^(8e) and R^(8f) is an unsubstituted C₁-C₈alkyl or hydroxyl; or a pharmaceutically acceptable salt thereof.
 7. Thecompound of claim 6, wherein X⁷is CR^(4a) where R^(4a) is H and R⁴is H,halo or unsubstituted C₁-C₈ alkyl; or a pharmaceutically acceptable saltthereof.
 8. The compound of claim 7, wherein Q is substituted orunsubstituted pyridyl; or a pharmaceutically acceptable salt thereof. 9.The compound of claim 5, wherein each R^(8c), R^(8d), R^(8e) and R^(8f)is H; or a pharmaceutically acceptable salt thereof.
 10. The compound ofclaim 9, wherein Q is substituted or unsubstituted pyridyl; or apharmaceutically acceptable salt thereof.
 11. The compound of claim 1,wherein the compound is of the formula (Ii-1):

wherein: R⁴ is halo or alkyl; R^(8e) and R^(8f) are independently H, OHor CH₃; and Q is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof.12. The compound of claim 11, wherein X⁷ is N, R^(8e) and R^(8f) are H,and Q is substituted or unsubstituted pyridyl; or a pharmaceuticallyacceptable salt thereof.
 13. The compound of claim 11, wherein X⁷ is CR⁴where R⁴ is H, R^(8e) is OH and R^(8f) is H or CH₃, Q is substituted orunsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.14. The compound of claim 1, wherein R¹ and R^(2a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or a pharmaceutically acceptable salt thereof.
 15. The compoundof claim 14, wherein X⁷ is CR^(4a) where R^(4a) is H; or apharmaceutically acceptable salt thereof.
 16. The compound of claim 15,wherein Q is substituted or unsubstituted pyridyl; or a pharmaceuticallyacceptable salt thereof.
 17. The compound of claim 14, wherein X⁷ is N;or a pharmaceutically acceptable salt thereof.
 18. The compound of claim17, wherein each R^(8c), R^(8d), R^(8e) and R^(8f) is H, and Q issubstituted or unsubstituted pyridyl; or a pharmaceutically acceptablesalt thereof.
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of:


20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ and R^(10a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety.
 21. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(3a) and R^(10a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) aretaken together to form a moiety selected from the group consisting ofthe structures:


23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b)are taken together to form a moiety selected from the group consistingof the structures:


24. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b)are taken together to form a moiety selected from the group consistingof the structures:


25. A pharmaceutical composition comprising (a) a compound of claim 1 ora pharmaceutically acceptable salt thereof and (b) a pharmaceuticallyacceptable carrier.
 26. A pharmaceutical composition comprising (a) acompound of claim 5 or a pharmaceutically acceptable salt thereof and(b) a pharmaceutically acceptable carrier.
 27. A pharmaceuticalcomposition comprising (a) a compound of claim 22 or a pharmaceuticallyacceptable salt thereof and (b) a pharmaceutically acceptable carrier.28. A kit comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and instructions for use.
 29. A kit comprising acompound of claim 5 or a pharmaceutically acceptable salt thereof andinstructions for use.
 30. A kit comprising a compound of claim 22 or apharmaceutically acceptable salt thereof and instructions for use.